MIC Genes: From Genetics to Biology

IMMUNOLOGY V76 - AP - 5175(D) / C1-1 / 09-14-00 08:23:12

ADVANCES IN IMMUNOLOGY, VOL. 76

MIC Genes: From Genetics to Biology SEIAMAK BAHRAM Centre de Recherche d’Immunologie et d’He´matologie, Strasbourg, France

I. Introduction

The specific interaction between the 움/웁 T cell receptor (TCR) and a peptide-bound major histocompatibility complex (MHC) molecule triggers the adaptive immune response (Garboczi and Biddison, 1999; Zinkernagel and Doherty, 1979). MHC class II (MHC-II) molecules present endosomally derived peptides of 12–18 amino acids in length to CD4⫹ helper T lymphocytes (Cresswell, 1994; Germain and Margulies, 1993), whereas MHC-I glycoproteins display endogenously generated nonameric amino acid chains to CD8⫹ cytotoxic T cells (Townsend and Bodmer, 1989; Yewdell and Bennink, 1992). As crucial as the latter reaction is to cellmediated immunity, it uses only a fraction of the available MHC-I molecules. These so-called classical, or class Ia, glycoproteins are encoded by MHC-linked genes, first identified in the mouse model through landmark serological and genetic experiments (for a review, see Snell, 1981; see also Gorer, 1936, 1937; Snell, 1948) and subsequently evidenced in humans, by studying alloimmunized individuals (for a review, see van Rood, 1993; see also Dausset, 1958, 1981). The universality of this system has been verified in almost every vertebrate species examined: In all, a restricted set of ubiquitously expressed, highly polymorphic, 웁2-microglobulin (웁2m)–associated, peptide-loaded class Ia molecules engages a large, almost combinatorial, T cell repertoire (Bjorkman and Parham, 1990; Du Pasquier and Flajnik, 1999; Litman et al., 1999). There are three such classical MHC-I genes in humans: HLA (human leukocyte antigen)–A, –B, and –C, encoded within the MHC on the short arm of the sixth chromosome, band p21.3 (Carroll et al., 1987; Dunham et al., 1987; Malissen et al., 1982). An equivalent number is carried by the mouse MHC on chromosome 17, designated H2-K , -D, and -L (Hood et al., 1983; Weiss et al., 1984).1 Structurally homologous to this first group of molecules are proteins encoded by what is termed nonclassical, or class Ib, MHC genes (Flaherty et al., 1990; Stroynowski, 1990). These are oligomorphic at best, most have an erratic pattern of tissue expression, and they display nonconventional 1 These two species are evidently the best studied with regard to MHC genetics and biology. For a description of MHC genetics in other species, the reader may consult Trowsdale (1995).

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peptide antigens (mainly hydrophobic polypeptides derived from class Ia signal sequences). The human MHC contains three such genes: HLA-E (Koller et al., 1988), -F (Geraghty et al., 1990), and -G (Ellis et al., 1990; Geraghty et al., 1987; Srivastava et al., 1987), whereas the murine H2 complex is replete with the H2-Q, -T, and -M sequences (with numbers varying from a few to several hundred if not thousands, depending on the haplotype) (Amadou et al., 1999; Delarbre et al., 1992; Teitell et al., 1994).2 The past 20 years have allied the term specialized with MHC-Ib antigens, the murine TL and M3 proteins being the most extensively studied (Lindahl et al., 1997; Shawar et al., 1994; Teitell et al., 1994). However, a unified function has begun to emerge for some of these nonclassical molecules as the interaction with a distinct set of immunoreceptors has been established (Braud et al., 1999; O’Callaghan and Bell, 1998). Indeed, human HLA-E along with mouse Qa-1 interact with the natural killer (NK) cell inhibitory complex CD94/NKG2A-E (Braud et al., 1998; Lee et al., 1998), and human HLA-G is recognized by immunoglobulin (Ig)–like receptors (Allan et al., 1999; Colonna et al., 1997; Ponte et al., 1999) (no function has been ascribed as yet to HLA-F ).3 Hence, ‘‘nonclassical’’ molecules are becoming more and more ‘‘classical’’ (albeit playing a different part), and the enduring usage of this terminology has become more a matter of semantics than as a function-based 2

In general, there seem to be fewer structural constraints on these MHC-Ib genes, and one can confidently state that the actual physical size of the MHC is more or less determined by the topology of these genes along the chromosome. Indeed, molecular genetic analysis of the MHC region in various species clearly reveals a colinearity of the remainder of the complex; that is, most, if not all, class II and III genes chart at regular intervals a segment of roughly 1 Mb each, whereas the class I region varies in length from only a few kilobases in the Syrian hamster to 1.8 Mb in humans. However, this is mainly true in mammals, whereas in the chicken, for example, the MHC seems to be much more compact and to contain only the appropriately designated ‘‘minimal essential genes’’ (Kaufman et al., 1999). 3 Besides the proposed crucial role of HLA-G at the maternofetal interface—that is, protection of the fetus (allograft) (by a still to be experimentally proven mechanism) from rejection exerted by maternal NK or T effector cells—the molecule does not stand the test of time. Indeed, no murine homologue has been reported as of yet; moreover, the HLAG orthologue detected in nonhuman primates, for example, the rhesus monkey (MamuG ), is a pseudogene (Boyson et al., 1996), despite the fact that a functional homologue, Mamu-AG, might perform a similar function (Boyson et al., 1997). Moreover, a rather frequent human HLA-G null allele has been identified (Ober et al., 1998). The same study reported an adult individual homozygous for this allele as well as a first-trimester placenta carrying this allele, with no detectable HLA-G protein. All in all, the physiological relevance of NK–HLA-G interaction awaits further confirmation, and the much stressed unique placental expression of HLA-G might be fortuitous rather than essential.

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rational nomenclature.4,5 In sum, this first family of MHC class I genes has evolved to interact with two essential effector cell types of the immune systems: T lymphocytes and NK cells. The cloning of the first non–MHC-encoded class I molecule, CD1, was quite unexpected (Calabi and Milstein, 1986), yet more members soon followed (in chronological order): zinc-움2-glycoprotein (Zn움2gp, alternatively designated ZAG ) (Araki et al., 1988), neonatal Fc receptor (FcRn) (Simister and Mostov, 1989), MHC class I–related (MR1) gene (Hashimoto et al., 1995), the endothelial cell protein C/activated protein C receptor, EPCR (Fukudome and Esmon, 1995), and finally the HFE molecule (Feder et al., 1996) (Fig. 1 and Table I). At the outset, most of these molecules were regarded as mere curiosities. However, important functions were quick to emerge for some of them. The most intensely studied member of this group, CD1, is also the only one with a clear immunological mission. Indeed, work in the past decade has clearly established the capacity of this molecule to present mycobacteria-derived lipidic or glycolipidic antigens to the 움/웁 TCR, and thus intervene in host defense (Porcelli, 1995; Porcelli and Modlin, 1999). Other members of this group, however, perform non–defenserelated yet essential functions. FcRn fuels the neonatal bloodstream with much-needed antibodies by transepithelial shuttling of maternal IgG in the gut and the placenta (Simister et al., 1997). The HFE molecule, identified while Feder and colleagues (1996) were investigating the genetic basis for HLA-linked hereditary hemochromatosis, plays a critical role in regulating the body’s iron content. In fact, most patients with primary hemochromatosis carry, at homozygosity, a point mutation within the membrane-proximal 움3 domain of the HFE molecule, rendering association with 웁2m and subsequent surface expression impossible, which leads to gradual iron overload (Bahram et al., 1999; Zhou et al., 1998). ZAG is a soluble 웁2m-independent glycoprotein enriched within various exocrine fluids and might carry a ‘‘fat-depleting factor’’ yet to be identified (Araki et al., 1988; Sanchez et al., 1992; Todorov et al., 1998). The biology and function of MR1 remain to be investigated 4 Indeed, by virtue of their primary sequence (⬎70% sequence identity to class Ia molecules) as well as tridimensional structures so far resolved for HLA-E (O’Callaghan et al., 1998), they are confoundingly similar to class Ia molecules. 5 The imagination of a number of authors has been extremely fertile, as the ‘‘nonclassical’’ genes have been further classified into ‘‘MHC-Ib’’ (HLA-EFG ), ‘‘-Ic’’ (MICA, MICB, and HFE ), or ‘‘-Id’’ (CDI, FcRn, and ZAG ) by Hughes (1999), for some renamed ‘‘class IV’’; this includes both MICA/B and TNF loci (Gruen and Weissman, 1997), or even those termed ‘‘neoclassical’’ (H2–M3) (Wang and Lindahl, 1993). Finally, one is perhaps still better off using the terms classical and nonclassical.

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(Riegert et al., 1998). Finally, the functional significance of EPCR within the blood coagulation cascade awaits further experiments. Therefore, a unifying view of the cross-genome scattering of MHC-I genes tends to define the MHC-linked members as those performing immunological functions, in contrast to most extra–MHC-encoded loci as engaged in non–defense-oriented roles. The recent identification of a distinct family of intra–MHC-located class I genes fits well with this dichotomy. Members of this MIC (MHC class I chain–related) gene family are stationed along the entire 1.8-Mb MHC class I region (Bahram et al., 1994). Unusual by several criteria (eg, a low degree of homology to other MHC-encoded class I genes, distinct transcriptional control elements, and a peculiar pattern of polymorphism), they appear to interact with T or NK cell receptors. The purpose of this chapter is to describe the short but already rich history of this novel family of histocompatibility antigens. II. Genes and Genomics

A. GENES MIC loci are the latest and the final HLA-encoded class I loci to be identified (Bahram et al., 1994). Their cloning was the culmination of a classic reverse-genetics approach using a 176-kb genomic contig linking HLA-B to BAT-1 in the middle portion of the MHC as a probe. Sequential screening of a fibroblast cDNA library with whole cosmid inserts ultimately led to the isolation of MICA and MICB cDNA clones. Genomic Southern blotting subsequently localized MICC, -D, and -E loci in close proximity to HLA-E, -A, and -F, respectively (Bahram et al., 1994) (Fig. 2). The MICA gene is merely 46.5 kb from HLA-B. MICB is 83 kb centromeric to MICA, and therefore ⬍130 kb from HLA-B. MICC is located 70 kb telomeric to HLA-E; MICD, 28 kb centromeric to HLA-A; MICE and MICG between HLA-G and -F, 18 and 85.5 kb centromeric to the latter, respectively; and finally, MICF, identified 24 kb centromeric to HLA-G (Shiina et al., 1999).

FIG. 1. Genomic dispersion of major histocompatibility complex (MHC) class I molecules. Debuting from an elusive MHC-I protogene, the present mammalian genome harbors class I homologues on at least five or six (human HFE is MHC-linked, unlike the murine counterpart) distinct genomic locations. This schematic representation is not to scale, and within multigene families (HLA, MIC, H2, CD1, as well as RAEs and ULBP), loci are positioned alphabetically. H2-QTM loci depict multiple genes. RAE-1␦ appears within parenthesis as it still needs to be confirmed as an independent locus and not an allele of other RAEs. References are included within the main text.

37 46 42 39a 46 69

CD1D FcRn ZAG MR1 EPCR UL18

No No

Yes Likely Likely Yes No No (?) No No

CD8 Yes Yes Yes Yes No No (?) No No

TAP

No No (?) ? ? ? ? (No) ? ?, Unlikely ?, Unlikely ?, Unlikely Yes ? ?

No Yes No

Yes Yes Yes Yes No No (?) Yes Yes

웁2m

Intestine Intestine Exocrine fluids Ubiquitous Endothelium CMV infection

Ubiquitous Ubiquitous Restricted—B cells Placental trophoblasts Epithelia Epithelia Intestine Myeloid lineage

Expression Cytosolic peptide MHC-I signal peptide ? Cytosolic peptide Nonpeptidic, if any Nonpeptidic, if any None Glycolipids (e.g., GMM and LAM) 움-Glycosylceramide/GPI None Fat-depleting factor ? ? Peptide

Cargo

Allele 165/327/88 5 1 14 52 16 ? (mutations) — ? ?/— ?/— —/ ? ? —

Ligand 움/웁 TCR/KIR2D, -3D CD94/NKG2A ? KIR2DL4/ILT? 웂/␦ TCR/NKG2D 웂/␦ TCR/NKG2D TfR 움/웁 TCR DN/CD8⫹/웂␦움/웁 TCR DN or CD4 IgG ? ? Protein C LIR-1/ILT2

웁2m, 웁2-Microglobulin; CMV, cytomegalovirus; GMM, glucose monomycolate; GPI, glycosylphosphatidyl inositols; IgG, immunoglobulin G; ILT, immunoglobulin-like transcript; LIR-1, leukocyte immunoglobulin-like receptor-1; LAM, lipoarabinomannan; LM, lipomannan; TAP, transporter associated with antigen processing; TfR, transferrin receptor. a Calculated molecular weight.

42 42 42 40 60–70 43a 49 43–49

HLA-A, -B, -C HLA-E HLA-F HLA-G MICA MICB HFE CD1A, -B, -C

Molecular Weight

TABLE I BRIEF CATALOG OF SEMINAL FEATURES OF MHC CLASS I GENES

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Both MICA and MICB are unusually large genes of 11,722 and 12,930 bp, respectively, compared to the average 3.5-kb HLA-A to -G genes (Bahram et al., 1996a,b). However, their overall genomic structures parallel those of the canonical MHC-I and more generally members of the Ig superfamily, in which distinct functional domains are encoded by separate exons (Barclay, 1999) (Fig. 2). Peculiarities are restricted to the leading and lagging exons and introns. In both MICA and MICB, large introns of 6840 and 7352 bp, respectively (versus ⬍200 bp in HLA-A to -G ), separate the first two exons and unique exons encode both cytoplasmic tails and 3⬘untranslated segments. Moreover, with respect to MICA, MICB contains an additional (unique) 1-kb 3⬘UT sequence (which incidentally eases transcript identification on Northern blots). The transcriptional–translational significance of these singularities, if any, is presently unknown. MICC, -D, -E, -F, and -G are pseudogenes of 4623, 1928, 7650, 1800, and 2627 bp, respectively (Shiina et al., 1999). Note that the MICG locus is presently available only in GenBank (accession No. AF055066). The truncated MICC gene is devoid of the first exon and intron and carries multiple in-frame termination codons. The crippled MICD gene lacks, in addition to the premier exon and intron, exon 6 and carries insertions or deletions within exon 5. The least problematic MIC pseudogene, MICE, contains all the exons but has multiple deletions both in exons 3–4 and across most introns. Finally, a part of intron 5 as well as exon 6 define the tiniest MIC pseudogene, MICF, as well as MICG. The possibility that some of these loci (especially MICE ) are operational in certain HLA haplotypes, as is the case for other MHC genes, remains to be investigated.6 B. GENOMICS The past 15 years have witnessed the progressive accumulation of a number of related sequences within the MHC, prominent of which are the class I and II multigene families (MHC Sequencing Consortium, 1999).7 Simplistic examination of these two gene families intuitively indicates that they originated from a common ancestor; however, lack of concrete data 6 Indeed, in two circumstances—MHC-II HLA-DRB and MHC-III C4/CYP21 genes— different HLA haplotypes carry a diverse load of genes and pseudogenes (for an overview, see the MHC Sequencing Consortium, 1999). 7 In addition to these, the HLA complex contains the following functional gene clusters: TAP (transporter associated with antigen processing) 1 and 2, LMP (low-molecular-weight polypeptides) 2 and 7 peptide delivery machinery within the class II region, the complement C4A and -B, the 21-hydroxylase (CYP ) A and B, the HSP701, 2, Hom stress protein genes, and finally the cytokines tumor necrosis factor (TNF ), lymphotoxin (LT ) A and B genes within the class III region, as well as the olfactory receptor gene complex on the telomeric side of the class I region. Other multigene families embedded in the class I region are also described within the text.

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FIG. 2. MIC genes and pseudogenes are stationed along the entire major histocompatibility complex (MHC) class I region. Genomic structures of all loci are highlighted. Data were extracted from the full sequence analysis of the MHC class I region (Shiina et al., 1999). MICA and MICB encode functional glycoproteins. MICC-G are pseudogenes. L, leader; TM, transmembrane; Cyt., Cytoplasmic tail; UT, untranslated.

has precluded definitive conclusions thus far.8 The recent completion of the entire MHC nucleotide sequence provides the much-needed infrastructure to draw an accurate picture of the molecular genealogy of this complex genomic segment. Indeed, this analysis, applied to the class I segment, readily depicts a plausible molecular scenario as to kinetics of the 2-Mb MHC-I region genesis. In brief, shotgun sequencing of a multiplex (YAC, BAC, PAC, and cosmid) contig linking the centromeric MICB gene to the telomeric HLA-F locus allowed Shiina and colleagues (1999) to establish the molecular identity of the entire 1,796,938 bp of this genomic stretch.9 Dot matrix analysis using this entire 1.8 Mb versus itself revealed numerous large-scale duplications. These include the following noticeable homology sections: (i) 35-kb downstream segment of both HLA-B and HLA-C genes as well as 35-kb upstream regions of MICA and MICB genes display 80% and 85% nucleotide identities, respectively; (ii) 앑39 kb upstream of MICD and 35 kb 5⬘ of MICE share significant nucleotide identity not only between themselves but also with (⬎50%) corresponding regions of MICA and MICB loci; and (iii) the 5⬘ segments of MICD and MICF are also homologous to each other. In sum, the upstream segments of all members of the MIC gene family (except MICC ) display sequence homology to each other over distances ⬎15 kb. Interestingly, all these MIC-linked homologous segments share a unique mix of genes, all members of several multigene families. These 8

It is beyond the scope of this chapter to cover the genesis of MHC-II genes, which incidentally might have taken a less ‘‘tormented’’ route than their class I counterparts. Indeed, and as previously alluded to, compiling data from a large number of species reveals a near-perfect colinearity of MHC class II loci, in contrast to an apparent chaotic evolutionary path for the class I region. For example, human HLA-DP, HLA-DO, HLA-DM, HLA-DO, and HLA-DR hold their exact murine counterparts within H2-P, H2-O, H2-M, H2-IA, and H2-IE. Moreover, given the fact that there as been no evidence (so far) of any class II gene outside the MHC, in sharp contrast to the class I situation, it appears safe to state that class II molecules are an ‘‘MHC invention,’’ having most likely appeared later in evolution. 9 Moreover, this research localized a total of 127 genes or potentially coding sequences (one gene every 14.1 kb), as well as a wealth of microsatellites (758 in total). The latter will provide tools for high-resolution mapping of HLA class I–associated disease genes are readily applied to psoriasis vulgaris (Oka et al., 1999). See the work of Shiina and colleagues (1999) for a thorough description.

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are HCGIX, 3.8-1, P5, HCGIV, HLA class I, and HCGII (in this order and within the same gene orientation in most cases). These facts strongly imply that successive segmental duplication of this basic unit gave rise to the present human MHC-I system. A model based on these data and supported by dendrograms of various gene families provides a plausible sketch of MHC-I genesis. According to this model, the present telomeric segment of the MHC was most likely the ‘‘ground zero’’ of MHC conception, where HLA-F most possibly served as the proto–MHC-I locus, which in turn gave birth to the MICE and HLA-G genes upon duplication. The basic unit, including MIC, HCGIX, 3.8-1, P5, HCGIV, HLA class I, and HCGII, was therefore created. Two independent subsequent segmental duplications of this elementary unit simultaneously generated both the HLA-A–MICF and MICA–HLA-B segments. The latter gave birth to MICB and HLA-C genes after a single duplicative event. The next partial segmental duplication gave rise to the HLA-80–HCGIV-4 segment from the HLA-A–HCGIV-5 segment. Similarly, four subsequent segmental duplications, including partial ones, led to the present gene organization of the HLA class I region. The order of the generation of each gene predicted by this model is supported by dendrograms of the HLA class I, MIC, HCGIX, P5, 3.8-1, and HCGIV family members (Shiina et al., 1999). Altogether, it is clear that the present MHC was created by a process of gene duplication and selective extinction which may have given the immune system enough leverage to effectively fight the various waves of microbiological aggression encountered through its half-billion years of evolution. C. PHYLOGENY MHC molecules are believed to have appeared concomitantly with other elements of the adaptive immune system (chiefly the TCR and Ig’s) along with early vertebrates, for example, the jawed fishes (Gnathostomata), some 450 million years ago (Du Pasquier and Flajnik, 1999; Litman et al., 1999). All attempts to identify any similar structures in the evolutionary precedent jawless fishes (Agnatha) or nonvertebrates have failed.10 Within the family of MHC-I molecules, there appears to be a clear dichotomy between the evolutionary ‘‘prudent’’ MHC-Ia molecules in comparison to the ‘‘wilder’’ MHC-Ib genes. Indeed, it appears as if the former were passed along from one species to the next (along with their allelic repertoire) 10 Although MHC genes are a vertebrate invention, histocompatibility at a cellular level goes way back to sponges, for example, the colonial tunicate, Botryllus schlosseri (Magor et al., 1999; Weissman et al., 1999), if not to flowering plants (Burnet, 1971).

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(Figueroa et al., 1988; Lawlor et al., 1988), whereas the latter were largely ‘‘reinvented’’ within the life of each species (Trowsdale, 1995). The evolutionary conservation of MIC genes (with the apparent exception of rodents, as discussed below) clearly breaches this general rule. Indeed, initial zoo-blotting experiments using a human MICA cDNA probe detected homologous sequences in a number of mammalian species. These included nonhuman primates as well as a number of more distant species, including goat, pig, cow, dog, and hamster. Curiously, mouse DNA appeared to be devoid of MIC-related sequences. Further experiments employing degenerate polymerase chain reaction (PCR) using not only congenic laboratory but also outbred mouse DNA as a template failed to reveal any remotely homologous sequences (V. Wanner, unpublished observations). Therefore, one can confidently state that mice (and hence probably rodents in general) are devoid of MIC genes, raising the question (and perhaps providing the answer) as to what extent MIC genes are dispensable (the question becomes even more difficult to evade once the issue of MIC-deficient humans is put forward later in the text). Obviously, from a phylogenetic point of view, mice are only one among thousands of mammalian species and are perhaps not the most interesting, as they appear to be a recent deviance from older rodents.11 To start with, the mouse H2 complex is unique. Besides the previously mentioned expansion–contraction phenomena observed in several congenic H2 haplotypes, one of the premier classical class I genes—indeed the most polymorphic, the H2-K locus—has been inexplicably ejected from the class I region and reinstated, by means of not yet understood phylogenetic gymnastics, to the centromeric segment of the class II segment (Amadou et al., 1999). Pertinent to our interest, the putative location of functional MIC (A and B ) genes in the mouse, the stretch linking H2-D (equivalent to HLA-B ) and BAT1, is substantially shortened as compared to the human MHC: 40 instead of 173 kb (Fig. 3). Hence, one can speculate that MIC genes were lost from the mouse genome during the H2-K translocation. Additional circumstantial evidence suggests that this very segment of the MHC may accommodate some structural frailty, as this is the precise segment where the MICA. gene is deleted in certain Southeast Asian HLA haplotypes (see below for details) (Fig. 3). Certainly, mice appear to be able to live and survive without any MIC genes. Two immediate conclusions, mutually exclusive, could be drawn from this observation: (i) MIC genes are not essential or (ii) they are replaced in this species by ‘‘functional 11 Obviously, this issue will be partially settled once various H2 haplotypes have been sequenced (Amadou et al., 1999) and totally laid to rest upon completion of the nucleotide analysis of the entire mouse genome (http://www.informatics.jax.org/).

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FIG. 3. A possible explanation for deletion of MIC genes from the mouse H2 complex. The ‘‘natural’’ BAT1–HLA-B interval is compared to that of some of HLA-B*4801 haplotypes as well as to a syntenic H2 segment. A large (100-kb) deletion eliminates MICA from some B48 haplotype mirrored by a shortened segment in the H2 complex. These events indirectly suggest fragility within this segment of the major histocompatibility complex (MHC). Caution should be instilled, however, as this contention is based solely on structural knowledge of the human and mouse MHCs.

orthologues’’ yet to be identified.12 In favor of the first possibility is that even humans tend to live a ‘‘normal’’ life without MICA and MICB (see the Section V for an explanation). In favor of the latter, there is at least one precedent: HLA-E and Qa-1. Despite not sharing any particular homol12 The use of the term essential could be open to debate. In nonimmunological science, the best example would perhaps be the eukaryotic developmental biology (this is not to get in the prokaryotic world); for a gene to be ‘‘essential’’ means that the natural or targeted removal of the locus from the germline will result in embryonic lethality. However, following this stringent definition, few ‘‘essential’’ genes function specifically within the immune system. Indeed, few ‘‘immune genes’’ are able to make such dramatic statements, and for most, their absence results in more or less serious postnatal complications, with some having no apparent effect at all (Schorle et al., 1991). Examples include that of TAP genes with bronchopulmonary (Donato et al., 1995) and other autoimmune manifestations (MoinsTeisserenc et al., 1999) and those of class I and II genes which result in various degrees of infectious troubles (Frelinger and Serody, 1998; Grusby and Glimcher, 1995; Grusby et al., 1993; Mach et al., 1996).

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ogy (i.e., they are no more homologous to each other than, say, HLA-E and Qa-2), they both perform similar tasks—presenting MHC-Ia signal peptides to the NK cell inhibitory receptor CD94/NKG2. In addition to humans, the sole species for which high-resolution molecular genetics data are available with respect to MIC genes is the pig (Velten et al., 1999). A sequence-ready contig of the SLA complex has revealed, besides the precise location of a large number of typical class I genes, two MIC-related sequences flanking several class I–related SLA genes on a segment syntenic to the human MHC, within the border between the class I and III segments, close to the pig TNF and BAT1 loci. The pig MIC genes show 앑70% homology to human MIC and no more than 20% to SLA class I sequences (Velten et al., 1999). The initial Southern blot experiment (Bahram et al., 1994) revealed an equivalent number of fragments in nonhuman primates. Efforts by a number of laboratories have culminated in the sequence analysis of these genes (Pellet et al., 1999; Seo et al., 1999; Steinle et al., 1998) (Fig. 4 and Table II). Surprisingly, the degree of sequence identity between human and primate MIC is far lower than that of respective class Ia sequences: 70% for the former versus 앑95% (or higher) for the latter. Moreover, there are several small (3–, 4–, or 5–amino acid) deletions within the 움1 and 움2 distal putative ligand-binding domain of nonhuman primate MIC sequences. No such deletions have been detected within the 움3 domain. Not surprisingly (as is the case for most class I genes), the transmembrane and cytoplasmic domains show the lowest degree of interspecies as well as interlocus conservation. Whether all these divergences reflect functional adaptation to a yet to be identified ligand or instead represent, more generally, a glide toward evolutionary inactivation remains to be appreciated. All in all, the clear conservation of the MIC gene family across mammals defines them as a distinct lineage of MHC-I genes, the eighth, following MHC-Ia/b, CD1, MR1, ZAG, FcRn, HFE, and EPCR. The apparent absence of MIC orthologues/homologues in the mouse genome, mirrored by the reciprocal lack of murine nonclassical loci in other mammals/vertebrates, might best serve as a trace for better understanding the evolutionaly dichotomy of these two well-studied MHC architectures. III. Transcripts and Transcription

A. TRANSCRIPTS The MICA gene encodes an mRNA of 1382 bp harboring a 1149-bp open reading frame that gives rise to a 383–amino acid polypeptide (this length varies based on the number of alanine repeats within the transmem-

FIG. 4. Primate and porcine MIC sequences. Domain-by-domain multiple alignment of the presently available primate and pig (only the 움1 exon) MIC sequences. When more than one locus has been identified, they are called MIC1 and MIC2, as the sequences do not show, in general, indisputable MICA- or MIC B-ness. In some cases, allelic variants have also been identified. Data were compiled from Pellet et al. (1999), Seo et al. (1999), and Steinle, et al. (1998).

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FIG. 4. (Continued )

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FIG. 4. (Continued )

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TABLE II HUMAN, PRIMATE, AND PORCINE MIC SEQUENCES Sequence Human MICA Gene Full-length cDNA Human MICB Gene Full-length cDNA Primate MIC (Genes and cDNAs) Aotus trivirgatus MIC Ateles fusciceps MIC1 Ateles fusciceps MIC2 Callithrix argentata MIC Cercopithecus aethiops MIC Cercopithecus patas MIC Chlorocebus aethiops MIC1 Chlorocebus aethiops MIC2 Gorilla gorilla MIC Hylobates lar MIC1 Hylobates lar MIC2 Macaca mulatta MIC101 Macaca mulatta MIC102 Macaca mulatta MIC201 Macaca mulatta MIC202 Macaca mulatta MIC3 Pan panisus MIC Pan troglodyte MIC Papio hamadryas MIC1 Papio hamadryas MIC2 Papio sp. MIC Pongo pygmaeus MIC1 Pongo pygmaeus MIC2 Porcine MIC (Genes) Sus scrofa MIC1 (exon 2) Sus scrofa MIC2 (exon 2)

Accession

Reference

X92841 L14848

Bahram et al. (1996a) Bahram et al. (1994)

U65416 X91625

Bahram et al. (1996b) Bahram and Spies (1996)

AF055389 AJ242444 AJ242445 AF055390 AF045601 AF045602 AF055385 AF055386 AF045597 AF045596 AF045604 AF055387 AJ242439 AF055388 AJ242440 AJ242441 AF045598 AF055384 AJ242442 AJ242443 AF045603 AF045599 AF045600

Steinle et al. (1998) Seo et al. (1999) Seo et al. (1999) Steinle et al. (1998) Pellet et al. (1999) Pellet et al. (1999) Steinle et al. (1998) Steinle et al. (1998) Pellet et al. (1999) Pellet et al. (1999) Pellet et al. (1999) Steinle et al. (1998) Seo et al. (1999) Steinle et al. (1998) Seo et al. (1999) Seo et al. (1999) Pellet et al. (1999) Steinle et al. (1998) Seo et al. (1999) Seo et al. (1999) Pellet et al. (1999) Pellet et al. (1999) Pellet et al. (1999)

AF083661 AF083662

Velten et al. (1999) Velten et al. (1999)

brane segment; see below) of 43 kDa (Bahram et al., 1994). The MICB transcript of 2376 bp encompasses an open reading frame of equal length bearing 83% amino acid similarity to MICA. MICA and MICB share only an average 21%, 19%, and 34% identity in the 움1, 움2, and 움3 extracellular domains, respectively, with other MHC-I genes; other MHC-I loci, whether human, mouse, classical, or nonclassical, share close to 70% homology with each other (Bahram and Spies, 1996). The MICA and MICB glycoproteins are structured, as are all MHC-I molecules. The mature

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protein contains three extracellular domains (움1–움3) preceding a membrane anchor segment and a relatively short (42–amino acid) cytoplasmic tail. Despite the fact that no canonical targeting motif could be detected within this tail, analysis of an engineered deletion as well as that of a natural mutant lacking this domain has established its role in directing the molecule to the basolateral surface of polarized epithelial cells, the putative physiological emplacement of the MICA glycoprotein (Suemizu et al., unpublished data) (see below). The transmembrane exon does not offer more than the expected hydrophobicity (for length variation, see below). The Ig-like 움3 domain contains no unusual features except for the clear absence of a CD8 coreceptor binding site. The 움1 domain is slightly shorter (85 amino acids instead of 90) and the 움2 domain is barely longer (96 amino acids instead of 92) than MHC-Ia. Moreover, the presence of a large number of N-linked glycosylation sites (eight in MICA and five in MICB) contrasts with an invariant single such site, NX(86)S, within classical MHC-I molecules, incidentally absent in both MICA and MICB. Finally, in addition to the two MHC-I canonical disulfide bridges (i.e., between cysteines 96–164 and 202–259), MICA harbors a third bridge connecting cysteines 35 and 40 (Bahram et al., 1994; Li et al., 1999). The sole notable divergence between the MICA and MICB genes resides within their respective transmembrane exons. Indeed, in contrast to MICB, MICA harbors a short tandem repeat (STR) sequence encoding various numbers of GCT triplets (Mizuki et al., 1997). Based on the number of repeats, these are named (for alanine) A4, A5, A6, A9, A10 (PerezRodriguez et al., 2000), and finally, A5.1. The latter is identical to A5 except for an extra nucleotide insertion (GGCT), leading to a frameshift mutation causing a premature termination codon within the transmembrane exon (the genetics and biological significance of these alleles are discussed below). B. TRANSCRIPTION In contrast to the classical (and most nonclassical) MHC-I genes, MIC genes are not ubiquitously expressed.13 In fact, their transcripts are not 13 As previously mentioned, MHC-Ia genes, as exemplified by HLA-A, -B, and -C in humans show a ubiquitous pattern of expression within all nucleated cells of the organism, with the clear exception of the central nervous system, although the latter changes after viral challenge and the former is not a universal feature of the animal kingdom, as rabbit erythrocytes express MHC molecules (Gorer, 1936). Regarding human MHC-Ib genes, except for HLA-G, which shows a restrictive appearance within the placenta (Ellis et al., 1990)—despite a broader mRNA expression pattern (Ulbrecht et al., 1994)—both HLAE and -F display broader transcription and translation patterns. HLA-F is transcribed in various tissues, although at the cellular level, B cells carry the highest amount of the protein (Wainwright et al., 2000). Finally, HLA-E resembles true class Ia molecules with regard to extent of expression, as it is almost ubiquitously expressed (Geraghty, 1993).

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detectable (by means of total cellular RNA Northern blotting) in cells of lymphohematopoietic lineage. MIC are primarily transcribed in fibroblasts and epithelial cell lines as well as various (almost all) tissues harboring these cell types (Bahram et al., 1994, and our unpublished observations; see below). Moreover, at odds with the transcriptional enhancement of MHC-Ia and -II loci following treatment by type I/II interferons, MICA and MICB mRNA levels remain unaffected by these cytokines. In line with this, sequence analysis of upstream genomic sequences of both MICA and MICB loci failed to show any homologies within the well-studied MHCIa promoter sequences; in particular, no sign of the interferon response sequence was evident.14 Intriguing, however, was the presence of a short DNA segment with significant homology to heat shock protein (HSP) gene promoters (Groh et al., 1996). The core of this region is defined by the contiguous and inverse duplications of the pentanucleotide motif 5⬘– nGAAn–3⬘, known as the heat shock response element (HRE), which is common to a number of stress-induced genes, a prototype of which is the MHC-encoded HSP70 gene (⬍400 kb centromeric to MICA and -B ) (Sargent et al., 1989). HRE functions by attracting the stress transcriptional machinery, for which trimerization of the heat shock transcription factor 1 is paramount (for an overview, see Morimoto, 1998).10 The function of the MIC HRE elements has been assessed by shocking epithelial cells for various lengths of time at 42–42.5⬚C and monitoring the level of MICA/B message up-regulation and membrane expression. Transcriptionally, the situation is fairly straightforward. As little as 5– 10 min of heat treatment is enough to induce the transcription of MICA and especially MICB (which is expressed at lower levels in ‘‘healthy’’ cells). The strongest induction encountered so far occurred 1–2 hr poststress. Once the heat shock is removed, the RNA levels return to the basal state after 앑12–16 hr. All of this is somewhat unremarkable, as it faithfully follows the kinetics of HSP mRNA rise and fall, most likely via recruitment of the same transcriptional machinery, although at significantly lesser strength (⬍30 minutes of autoradiography is sufficient to detect changes in HSP transcription as compared to overnight exposures for MIC ). In the first experiments, no obvious correlation between higher MIC mRNA and membrane expression was noted (Groh et al., 1996). However, these early experiments were performed irrespective of the cells’ growth status; when 14 MHC-I transcription is reasonably well characterized (David-Watine et al., 1990; Kimura et al., 1986). In addition to a typical TATA and CAAT box, the critical region seems to reside around position ⫺150 from the transcription start site, where a number of overlapping motifs regulate the transcription. In addition to the above-mentioned interferon response sequence responding to type I (움 or 웁) and II (웂) interferons synergistically with TNF, these include ␬B1 and ␬B2 as well as retinoic acid X receptor 웁 (RXR-웁) binding sites.

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Groh and colleagues (1998) performed similar attempts in confluent (hence, quiescent) cell layers, a marked increase in MIC surface expression was obvious after heat shock. Actually, the physiological relevance of this experimental procedure is doubtful in that the intestinal epithelium is the fastest proliferating tissue in the body, second only to the skin; but it does clearly document, under certain circumstances, enhanced poststress surface deposition of MICA and possibly MICB. Finally, it remains to be seen to what extent MICs are induced by more ‘‘real-life’’ stressful challenges. Obvious examples include epithelial infections with bacteria such as Shigella, Salmonella, Listeria, and Chlamydia: parasites such as Cryptosporidium and Leishmania; and, finally, viruses such as influenza and vesicular stomatitis virus, among many other candidates. Although the presence of an HRE in the putative promoter region of MICA and MICB genes is intriguing, it is not unprecedented. Over a decade ago, during one of the first thorough characterizations of an MHC-I promoter, Kourilsky and co-workers (Kimura et al., 1986) recognized a sequence homologous to HRE in the promoters of the H2-Kb and -Ld mouse class I genes. Although this sequence is probably not functional, as typical MHC-I genes are not stress induced, it may represent vestigial imprints of the universal heat shock defense machinery on the adaptive immune system. IV. Biochemistry and Biology

A. BIOCHEMISTRY A number of anti-MICA/B–specific monoclonal antibodies (mAbs) (Groh et al., 1996, 1998; M. Colonna et al., unpublished observations) and antisera (Suemizu et al., unpublished data) have been obtained.15 These reagents have led to initial biochemical (Groh et al., 1996) and cell biological (Suemizu et al., unpublished data) assessment of MICA function. Indeed, cell surface staining as well as immunoprecipitation experiments using various B cell line transfectants has provided a number of important observations. (i) MICA cDNA stably transfected into 웁2m-deficient Daudi cells allowed detection of a cell surface MICA chain at levels comparable to that in C1R-transfected cells. Moreover, pulse–chase experiments following metabolic labeling revealed identical Endo-H resistance ki15 mAbs 56, 83, and 2C10 were obtained upon immunization with C1R–MICA transfectants (Groh et al., 1996). They are all of the IgG isotype and specific for MICA. mAbs 56 and 2C10 were employed in the biochemical characterization of MICA, whereas mAb 83 was used for immunofluorescent staining. Another mAb, 6D4, was subsequently obtained (Groh et al., 1998) and reported to interact with both MICA and MICB. This, together with 2C10, was used in target recognition experiments (Groh et al., 1998).

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netics for MICA molecules in both Daudi and C1R transfectants, proving that 웁2m is not required for physiological MICA cell surface expression. (ii) The same set of experiments performed in the TAP-deficient 5.2.4 cells revealed normal surface expression of MICA in the absence of cytosolic peptides. (iii) The native MICA chain is highly glycosylated, with a molecular mass of 65–75 kDa compared to 43 kDa after glycan removal. (iv) Attempts to extract peptides from the putative antigen binding groove were unsuccessful (Groh et al., 1998). This correlates well with the independence of MIC biology from the endogenous antigen presentation pathway as well as with the structure of the putative ligand binding cleft (see below). (v) Finally, staining with this first set of monoclonal antibodies suggested that MICA is specifically expressed in the gastrointestinal epithelium, as revealed by indirect immunofluorescence on tissue sections; the only other site of expression was thymic cortical epithelium (Groh et al., 1996). More recent experiments, however, document a more generalized pattern of expression for MIC genes, extending beyond the intestinal epithelium. This contention is based on two sets of experiments. First, an extensive tissue/ organ Northern blot experiment reveals the presence of both MICA and MICB transcripts in virtually every organ examined, with the clear exception of the central nervous system (unpublished observations). This is most likely due to the presence of epithelial cells within each of these positively examined organs, as initial experiments had documented patent MIC expression in epithelial or fibroblastic cell lines (Bahram et al., 1994; see above). Second, analysis of MIC expression with a novel set of anti-MICA or MICA/B mAbs (M. Colonna et al., unpublished observations) displays a much broader staining pattern; for example, various epithelial components of the kidney and the skin are positive, in contrast to the spleen, which is negative. Therefore, it appears that MIC expression is primarily controlled at the transcriptional level. This was hinted at by the fact that MICA and MICB glycoproteins can be invariably detected in various transfected cells of diverse lineages, for example, lymphoid (C1R, Raji, lymphoblastoid B cells, and so on) (Groh et al., 1996) or epithelial [HeLa (N. Fodil, unpublished observations) and MDCK (Suemizu et al., unpublished data)], strongly implicating that the presence of mRNA suffices for surface expression.16 Nevertheless, why some monoclonal antibodies give restricted staining patterns (our unpublished observations; Groh et al., 1996) remains to be thoroughly investigated. Besides the obvious bigenicity and polyallelism, the fact that both MICA and MICB are heavily glycosylated (perhaps differently in various tissues) should be considered as possible explanations. 16 The opposite is best illustrated by both HLA-E and -F, which do not reach the cell surface despite large levels of transcripts and intracellular deposits in the absence of their physiological ligand. This is known to be true in the case of HLA-E but remains to be proven for HLA-F.

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A mouse antiserum raised against MICA-expressing NS1 transfectants has allowed an initial analysis of MIC cell biology. Using indirect immunofluorescence, immunoelectron as well as laser scanning confocal microscopy, Suemizu and colleagues (unpublished data) were able to localize the MICA glycoprotein at the basolateral surface of human intestinal epithelial cells, one of the putative sites of MICA function. Moreover, subcellular localization studies of an exon 6 (cytoplasmic tail)–less MICA cDNA construct as well as one containing the MICA A5.1 allele establish a function for sequences contained within the MICA (and possibly MICB) cytoplasmic tails for intracellular targeting of the glycoprotein, as following its removal the molecule was diverted to the apical cell membrane. Consequently, MICA A5.1 could be considered de facto a MICA null allele. B. LIGANDS Prior to reviewing MIC ligands, it is perhaps useful to put into perspective the long and often passionate field of MHC-Ib and 웂/␦ and other ‘‘exotic’’ T cell types. Shortly after the discovery of 웂/␦ T cells in humans (Brenner et al., 1986, 1988), Strominger (1989) made a provocative prediction. The thesis postulated that two (then and, in large part, today) enigmatic components of the immune system, that is, 웂/␦ T cells and nonclassical class I molecules (dubbed here MHC-Ib), might interact with each other. What followed [indeed slightly preceded (Matis et al., 1987)] was a constant stream of reports linking these two entities in various systems. The most conclusive efforts were achieved, for obvious experimental reasons, in the murine system.17 A classical example is the description by Tonegawa and 17 The reader is urged, however, to consider fundamental differences in 웂/␦ T cell biology in various species [for detailed information about 웂/␦ T cells, the reader is referred to a number of authoritative review articles which have already fielded the subject (Allison and Havran, 1991; Bluestone et al., 1995; Chien et al., 1996; Kaufmann, 1996)]. First, whereas in humans, 웂/␦ T cells carry a diverse repertoire and are more or less evenly distributed throughout the body (Groh et al., 1989), in the mouse several subpopulations carry a biased TCR (preferential usage of certain V segments, albeit for the fact that they carry a high degree of junctional diversity). The latter are restricted to certain anatomical sites (e.g., the skin, tongue, vagina, and intestinal epithelia), where they represent the majority of T cells and hence are believed to act as the so-called first line of defense. Second, and despite the fact that in both humans and mouse 웂/␦ T cells constitute a rather minute fraction of peripheral T cells (⬍10%), in other species such as cattle, sheep, and chickens, they tend to outnumber 움/웁 T cells within the circulation. Third, in spite of major advances during the last few years, a universal 웂/␦ ligand has yet to be found. In fact, it is becoming increasingly clear that such a ligand may not exist, as these receptors appear to interact with antigen much like Ig. Considering the known ligands, two categories of molecules could be recognized. Despite the formal absence of the paradigmatic 움/웁 MHC restriction (Zinkernagel and Doherty, 1979), MHC and MHC-like structures have been shown to interact with the 웂/␦ TCR. Also, specifically with respect to human 웂/␦ T cells, the situation

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colleagues of the recognition of H2-T22b (originally named TL 27b) by a 웂/␦ T cell clone (KN6) (Bonneville et al., 1989; Ito et al., 1990). The same molecule was further recognized by another famous 웂/␦ clone, G8 (Schild et al., 1994).18 Besides T22, G8 has also been shown to interact with another murine class Ib chain, T10 (Schild et al., 1994), highly homologous to T22. Another instrumental T cell clone, LBK5, recognizes the class II molecule H2-IEk (Schild et al., 1994), independent of any species or cell type ‘‘barrier,’’ as the recognition is equally potent with human, mouse, or hamster models or in T, B, or fibroblast cell lines. The recognition of nonclassical MHC molecules by the 웂/␦ TCR occurs independently of the wellunderstood class I and II antigen processing pathways, as HLA-DM or TAP mutant cell lines (RMA-S, 721.134, or T2) are equally good stimulators in comparison to wild-type parental lines (Kaliyaperumal et al., 1995).19 Indeed, the sole unequivocal modulator appears to be the level of cell surface expression; even bacterially expressed plastic-bound molecules are able to stimulate a 웂/␦ hybridoma (Crowley et al., 1997). Another murine has been greatly clarified. The human V웂9 (or V웂2, depending on the nomenclature)/V␦2 T cells (these constitute ⬎90% of circulating 웂/␦ cells) respond to a group of phosphatecontaining small molecules, independent of any MHC element (Constant et al., 1994; Morita et al., 1995; Schoel et al., 1994; Tanaka et al., 1994). The fact that several microbiological extracts carry these elements has led to the assumption that this interaction might be in line with the defense role for these cells, which indeed augment numerically during the course of various infectious states (Balbi et al., 1993; Caldwell et al., 1996; Hara et al., 1996; Perera et al., 1994). However, despite the apparent logic in this interaction, it is restricted to human cells, as mouse 웂/␦ T cells do not recognize any of these molecules (M. Bonneville, personal communication). Finally, added to this list of ligands are more ubiquitous molecular entities such as alkylamines derived from a vast spectrum of biological taxa such as microbes, plants, and tea (Bukowski et al., 1999). Hence, we are left with a heteroclitic catalog of targets diverse in both size and structure. 18 A more recent report has evidenced, for the first time, physical interaction between MHC-Ib and a 웂/␦ TCR, that is, binding of H2-T22b to the immobilized G8 protein (Crowley et al., 2000). This, along with the concomitant structural resolution of T22b, allowed the authors to map a putative interaction site with the 웂/␦ TCR on opposite sides of the T22 groove, where the 웁-pleated sheets are directly exposed and on a diametrically opposite acidic patch. This is different from the site proposed by the Strong group (Li et al., 1999) for MICA to interact with the V␦1 receptor: under the 웁-sheet. This situation is very distinct with respect to the MHC-Ia–움/웁 interaction. Thus far, all published crystal structures show a nearly identical picture, that is, an 움/웁 TCR sitting diagonally across from a peptide–MHC complex (Ding et al., 1999b; Garboczi et al., 1996; Garcia et al., 1996, 1998; for a review, see Garcia et al., 1999). 19 This is in contrast to earlier experiments, which incriminated peptide dependency of the 웂/␦ recognition. This was based on site-directed mutagenesis experiments. Once applied to several residues on the floor of the putative antigen-binding cleft of T22, this affected recognition by the KN6 hybridoma (Moriwaki et al., 1993). However, this might have been the indirect consequence of surface expression, as documented by others regarding at least one of these point mutations (Chien et al., 1996).

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MHC-Ib molecule recognized by the 웂/␦ TCR is Qa-1. Vidovic and colleagues (1989) reported the isolation of a CD4⫺CD8⫺ TCR 웂/␦⫹ T cell hybridoma (DGT3) specifically recognizing Qa-1b in conjunction with a peptide ligand, the copolymer poly(Glu50Tyr50). Human MHC-reactive 웂/␦ T cell clones have not been scarce either; almost every HLA locus and a large number of alleles have been recognized as potential targets. Examples include clones stimulated by HLA-A2 (Spits et al., 1990), -A9 (Vandekerckhove et al., 1990), -A24 (Ciccone et al., 1989), -DR2 (Flament et al., 1994), -DR7 ( Jitsukawa et al., 1988), -DRw53 (Holoshitz et al., 1992), and -DQw6 and -DQw7 (Bosnes et al., 1990). Another well-known target for 웂/␦ T cells, including those within the gut, is CD1 (Balk et al., 1991, 1994; Bleicher et al., 1990; Blumberg et al., 1991; Kim et al., 1999; Somnay-Wadgaonkar et al., 1999). Even non-MHC structures can apparently be specifically recognized by 웂/␦ T cells; the most thoroughly studied case is certainly that of the herpes simplex virus glycoprotein, gl. Indeed, a series of elegant experiments by Bluestone and colleagues provides one of the most thorough investigations of the molecular details of 웂/␦ T recognition undertaken to date ( Johnson et al., 1992; Sciammas and Bluestone, 1998; Sciammas et al., 1994). The 웂/␦ T cell clone, Tgl4.4, recognizes gl independently of the class I and II antigen presentation pathways. This recognition is equally strong when a soluble recombinant protein is used. Hence, the same 웂/␦ TCR is able to recognize a large glycoprotein in a native configuration, reminiscent of Ig recognition of target antigen. Maybe the single most important message of research within recent years is that the 웂/␦ mode of recognition resembles Ig rather than 움/웁 TCR. As previously mentioned, and again resembling antibodies, 웂/␦ TCRs are able to recognize a great variety of molecular entities, ranging from small phosphate-bound molecules to large glycoproteins and englobing structures as disparate as alkylamines (Bukowski et al., 1999) and glycolipids. Finally, although the molecular drive behind this promiscuous mode of recognition has yet to be cracked by the crystallographic studies so elegantly applied to both TCR–MHC class I and II ternary complexes (Garboczi et al., 1996; Garcia et al., 1996; Reinherz et al., 1999), sequence analysis of the junctional diversity of 웂/␦ TCRs allows some educated insight into the ‘‘logic card’’ of the receptor.20 This work has shown that the 웂/␦ TCR is more similar to Ig than to the 움/웁 TCR in CDR3 length distribution (Rock et al., 1994). In 움/웁 TCRs, both CDR3s are relatively short and uniform in length, likely governed by coercive forces linked to dual peptide–MHC recognition, whereas in 웂/␦ TCRs, the 웂-chain CDR3 20 The recent resolution of the V␦ chain has indeed shown invaluable structural data and has confirmed previous results indicating a recognition mode similar to those used by Ig’s (Li et al., 1998).

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chain is short with a limited length distribution, but ␦-chain CDR3 loops are long and quite heterogeneous in length. This is very similar to the situation in Ig, where the light-chain CDR3 loops are short and homogeneous, but the heavy-chain CDR3 loops are longer with a wide length range. Hence, the 웂/␦ TCR could be considered a ‘‘T cell immunoglobulin.’’ The field of NK cells and MHC class I molecules has roots in much older times. The first link between the two entities has been the longstanding experiments of Cudkowicz, Bennett, and Kumar, who in early 1970s, described the so-called ‘‘hybrid resistance’’ phenomenon (Shearer and Cudkowicz, 1975; reviewed in Bennett, 1987; Cudkowicz and Hochman, 1979; Kumar et al., 1997). Briefly, whereas irradiated F1 hybrids between two H2-mismatched strains of inbred mice accept solid organ grafts from either parent, they tend to reject those of bone marrow. The molecular basis for this event was attributed to a hypothetical hematopoietic histocompatibility (Hh) locus which remained mysterious until the recent discovery of the interplay between a growing number of NK receptors and MHC-I molecules (Ka¨ rre and Colonna, 1998; Lanier, 1998). Indeed, two sets of NK and T cell subtype–specific receptors interact with a wide range of MHC-I loci and alleles through a site distinct from the well-known footprint of the 움/웁 TCR on MHC 움-helices and peptide. These receptors arise from two distinct gene families: the human chromosome 19q13.4-based Ig-like killer inhibitory receptors (KIRs), including KIR proper as well as the so-called Ig-like transcripts (ILTs) (Colonna, 1997; Lanier, 1998); and the 12p12–13–located CD94 (Lopez-Botet and Bellon, 1999), NKR-P1 (Lanier et al., 1994), and NKG2A-F lectin-type molecules (Houchins et al., 1997; Ryan and Seaman, 1997).21 Among KIRs, KIR2D (nD refers to the number of extracellular domains; for terminology, see Long et al., 1996) binds to HLA-C, and KIR3D binds to HLA-A and -B.16 ILTs may have a broader pattern of interaction with MHC-I glycoproteins; for instance, ILT-2 interacts with HLA-A, -B, and -G (Colonna et al., 1997). Although engagement of cognate MHC ligand by most receptors inhibits effector cell function via recruitment of SHP-1 and SHP-2 phosphatases by the cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM), certain receptors lack ITIM and associate with signal-transducing modules containing the immunoreceptor tyrosine-based activatory motif (ITAM). Within this context, Groh and colleagues have added MIC to the evergrowing list of 웂/␦ and NK ligands. Based on the intestinal pattern of expression obtained by mAb 83, these authors speculated that MIC might interact with a subset of T lymphocytes bearing the V␦1 웂/␦ receptor, 21 No equivalent to KIR genes have been identified so far in the mouse, where the major inhibitory receptor gene family is the chromosome 6–based lectin-type Ly49 molecule (Yokoyama, 1998), for which a human counterpart has been identified (Westgaard et al., 1998).

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enriched within this same anatomical site. To prove this, gut-derived T cells grown on C1R–MICA– or –MICB-transfected feeder cells were flowsorted using a V␦1-specific mAb. In this manner, two V␦1-bearing 웂/␦ T cell lines and several derived clones were shown to specifically recognize and kill target cells expressing MICA/B molecules (Groh et al., 1998). This recognition was shown to be independent of proteasome-generated, TAP-translocated cytosolic peptides, as lactacystin-treated (proteasomeinhibited) or TAP-deficient transfectants were lysed as well as controls by the same T cell clones. Moreover, attempts to extract peptides using the same conditions that allow peptide isolation from the MHC-Ia groove were unsuccessful. This work clearly establishes the ability of 웂/␦ TCR–bearing T cells to engage MICA- and MICB-expressing target cells, as both antiMIC and V␦1 antibodies were able to inhibit this interaction. However, this inhibition was only partial, and direct physical contact between TCR and MIC remains to be proven by TCR gene transfer experiments. Several other caveats also persist. Chiefly, as previously discussed, MIC expression does not match V␦1 expression and vice versa. Moreover, as the issue of alloreactivity of MIC-interacting T cell clones has not been addressed, the question remains as to their physiological significance. Finally, another recent contender, CD1c, has outcast MICA from the front scene (Spada et al., 2000). Indeed, the comprehensive effort by Spada and colleagues reported very convincing data, including direct TCR involvement in the recognition of CD1c by autoreactive V␦1-bearing 웂/␦ T cells. The situation became more interesting as Bauer and colleagues joined forces with Lanier and co-workers to demonstrate that a previously orphan NK cell receptor, NKG2D, interacts with MICA (Bauer et al., 1999). As previously mentioned, NKG2D is a member of a cluster of genes (NKG2A through F ) encoding type II transmembrane lectin-type molecules on the short arm of human chromosome 12 and murine chromosome 6. Among these, the well-known NKG2A partners with the closely linked CD94 (Lazetic et al., 1996) to create an inhibitory receptor on most NK and CD8⫹ 움/웁 T cells which recognizes the broadly expressed HLA-E molecule.22 By sequence homology, NKG2D is the most divergent member of the NKG2 gene family, as it shares only 20% sequence identify with other members of the family, which bear ⬎90% identity to each other. The gene, transcribed widely in T (CD8⫹ 움/웁 and 웂/␦) and NK cells, encodes a 42-kDa glyco22 NKG2C also associates with CD94, but in this case creates an activatory receptor. In contrast to inhibitory receptors engaging the signal transduction machinery through their cytoplasmic ITIM, the triggering receptors lack such a motif and hence have to recruit appropriate ITAM-bearing modules. For NKG2C/CD94, this is DAP12, a 12-kDa molecule Interacting with NKG2C in part via charged residues in their respective transmembrane segment (Lanier et al., 1998).

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protein, surface expression of which requires the presence of a signaltransducing unit called DAP10 (Wu et al., 1999) or KAP10 (Chang et al., 1999). DAP10 is both structurally and functionally analogous to as well as physically linked to DAP12, a molecule previously shown to bind CD94/ NKG2C, encoded on chromosome 19q13.1.23 Moreover, the very fact that NKG2D is widely expressed on 움/웁, 웂/␦, and NK cells indirectly questions the physiological relevance of the putative ‘‘exclusive’’ 웂/␦ T cell interaction with MIC (Groh et al., 1998). Finally, the presence of a murine NKG2D orthologue (in contrast to the case for MIC), suggests, at the very least, that MICA/B is not the only ligand for this receptor. This is corroborated by evidence for a promiscuous interaction of NKG2D with MHC-I molecules in general; soluble NKG2D binds to a cocktail of HLA-A, -B, and -C alleles (Ding et al., 1999a). Indeed, a major leap in the field was the identification of a distinct set of ligands for NKG2D. These somewhat remote MHC-I lookalikes are unique in that they lack the proximal 움3 domain. In mouse, these are products of the glycosyl-phosphatidyl inositol (GPI)-linked retinoic acid early transcripts RAE-1움, 웁, 웂, and ␦, as well as the H60 gene product, originally identified as a minor histocompatibility antigen (Cerwenka et al., 2000; Diefenbach et al., 2000). Human equivalents of these murine chromosome 10-encoded loci are located on chromosome 6q25 and were identified during Cosman and colleagues’ search for molecules interacting with the cytomegalovirus UL16 glycoproteins (Cosman et al., 2000) (Fig. 1). Three of these ULBPs (ULBP1-3) were originally reported; at least one more has been identified through in silico genomic screening (B. Cuillerier, O. Cle´ ment, S. B., unpublished observations). These molecules do not appear to be induced by cell stress, although some are strongly regulated by retinoic acid during embryonic development. For these transcripts to be absent from most adult tissues, and to be selectively expressed within tumor cells, might indeed represent a powerful signal for NK cell anti-tumor cytotoxicity. The fact that this new set of molecules is conserved between human and mouse, albeit quite remotely, reflects perhaps the redundancy of MIC recognition by NKG2D. In sum, MICA (and likely MICB) have been shown to interact with two distinct immunoreceptors, the 웂/␦ (V␦1) TCR and NKG2D (although effects attributed to V␦1 TCR could indeed be attributable to NKG2D); the physiological significance of these interactions remains a focus for future work. C. STRUCTURE The structure of a soluble MICA glycoprotein (allele 001) expressed in insect cells (Bauer et al., 1998) has been successfully analyzed by x-ray crystal23 An important note must be made, however. In contrast to ITAM-bearing DAP12 capable of transducing signal via interaction with Syk and ZAP70, DAP10 lacks ITAM but bears a YXXM motif binding phosphatidylinositol-3-kinase and Grb-2 molecules.

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lography at 2.8 A˚ (Li et al., 1999). The structure confirms the general configuration of the molecule within an MHC-I–fold (Bjorkman et al., 1987; Madden, 1995), that is, a membrane proximal Ig C-type 움3 domain and a distal putative ligand binding superdomain (움1, 움2) composed of an eightstranded, antiparallel, 웁-pleated sheet, topped by two somewhat parallel 움helices. Although the former does not reveal any surprises, the latter unveils an edifice that seems to have barely stood up to a ‘‘crash test,’’ a structure embodying the extreme sequence divergence from classical HLA molecules. The 움3 structure is unremarkable in that it closely parallels that of other MHC-I molecules as well as 웁2m itself. It is connected to the 움1움2 distal domain by a short minipeptide (L178–T181) which, unlike orthologous linker peptides in other class I sequences, is not in a helical conformation but follows an extended topology, which allows an interdomain flexibility unseen in any other class I structure. Indeed, the most remarkable feature of the MICA structure resides in the fact that the proximal and distal domains make no intimate contact with each other, as indicated by a 113.5-degree deflection (within the studied crystal) in comparison to the prototypic HLA-B27 molecule. However, this alone cannot explain the 웁2m independence of MICA expression, a characteristic shared only with the soluble ZAG. In fact, the crystal structure offers no real structural clues for the absence of 웁2m binding, and the authors (Li et al., 1999) finally attributed this to a catalog of events, including the large number of glycosylation sites (especially N8, although it is not conserved in MICB), lack of well-known 웁2m contact points, and the extreme flexibility of the distal and proximal domains. The 움1움2 cleft is similar to that of other class Ia (Bjorkman et al., 1987; Fremont et al., 1992; Garrett et al., 1989; Madden et al., 1991; Zhang et al., 1992) and Ib molecules (Lebron et al., 1998; Sanchez et al., 1999; Zeng et al., 1997), although an overall comparison reveals major contortions throughout the edifice (Fig. 5). Examples include the loop between the first two, as well as the hairpin connecting the third and fourth, 웁-strands. Deviations also occur within 움-helices. Helix 1 (H1) in the 움1 domain is longer than equivalents in other class I molecules, and hence structures as a well-defined entity.24 This is also the case for H1 and H2b in the 움2 domain, which collectively skew the structure of this domain toward that of the FcRn molecule. The 웁-strands do not deviate from their MHC-Ia counterparts, at least with respect to the six central ones. 24 Based on homology to other class I structures (HLA-B27 has served as a prototype), Li and colleagues divided the 움1 and 움2 domain helices into two and three ‘‘subhelices,’’ respectively. These are helices 1 (residues 45–54) and 2 (60–79) in the 움1 domain and 1 (137–150), 2a (structure not experimentally determined, but deduced), and 2b (164–170) in the 움2 domain.

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FIG. 5. MICA polymorphism plot. MICA polymorphic residues are highlighted (black) on the ribbon structure of MICA. The figure was generated using RasMol 2.7.1 and Adobe Illustrator with MICA coordinates extracted from Protein Data Bank (http://www.rcsb.org/ pdb/cgi/explore.cgi?pdbld⫽1B3J).

All in all, the MICA putative antigen-binding cleft is less spacious than that of class Ia molecules; the distance between the two helices (C움 trace) is as short as 10 A˚ within the first four 웁-strands and 7 A˚ across the second four as compared to ⬎18 A˚ for the classical H2-Kb. It is even narrower than that of non–peptide-binding CD1 (14.4 A˚ ) or the empty FcRn (10.2–12.9 A˚ ) and is only close to that of H2-T22b (Wingren et al., 2000).25 This is certainly in line with the failure of previous attempts to detect any MICA-associated peptides (Groh et al., 1998). Moreover, Li and colleagues (1999) did not encounter any extraelectron density (not accounted for by MICA or solvent), tending to establish that MICA does not enfold any cargo. However, this possibility will only be ruled out once the structure of a 15–amino acid segment (residues 147–161, corresponding to the 움2 H2a) has been established. Indeed, in the reported experimental conditions, residues 147–151 eluded structural resolution and hence had to be modeled assuming a 25 Initial reports suggested that CDId is capable of peptide presentation (Castano et al., 1995); however, the physiological relevance of this interaction has since come into doubt (Brossay and Kronenberg, 1999).

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polyalanine configuration, and amino acids 152–161 failed to reveal their spatial rearrangement. V. Genetics and Immunogenetics

A. DIVERSITY 1. Repertoire Polymorphism has been the driving force behind the discovery of MHC genes, in both mice and humans, and is perhaps the most fascinating feature of these molecules (Parham and Ohta, 1996). MHC-Ia are indeed the most polymorphic genes of the vertebrate genomes. Three hundred twenty-seven alleles have been documented for HLA-B, 165 for HLA-A, and 88 for HLA-C (Bodmer et al., 1999). This extraordinary diversity enables these molecules, at the population level, to present an infinite range of peptide antigens to T cells (Rammensee et al., 1993). It has been argued that this high degree of polymorphism is the result of overdominant selection exerted by infectious agents throughout mammalian evolution (Hill, 1998; Hughes and Nei, 1988).26 In contrast, MHC-Ib genes are oligomorphic at best, for example, 14 alleles are known for HLA-G (Ishitani et al., 1999), 5 for HLA-E (Geraghty et al., 1992), and none for HLA-F (for the latest listing, consult http:// www.anthonynolan.org.uk/HIG/index.html). This lack or low degree of diversity has been variously interpreted. Pamer et al. (1993) postulated that limited polymorphism enables them to present conserved microbial epitopes to the immune system,27 although for others the lack of polymorphism signifies their nonrelevance in an effective immune response (Klein and O’Huigin, 1994). However, in light of the recent discovery of what may be their raison d’eˆtre—interaction with a diverse, yet clonally unchecked NK repertoire—the whole body of literature and hence conclusions regarding these molecules require reappraisal. 26

Despite the fact that the most plausible driving force behind maintenance of MHC diversity is the selective force exerted by infectious agents, it is at the very least ‘‘troublesome’’ to see how relatively little association there is between HLA alleles and infectious threats (Hill, 1998). Indeed, the most notable HLA association is with autoimmune diseases, not infectious ones. Despite this notable degree of association, it is not easy to envision a role for such disorders in shaping the HLA repertoire as, in fact, these disorders affect individuals (at least until early in this third millennium) typically after the reproductive period. 27 Although this has been so far a circumstantial theory, it has been elegantly proven in case of H2–M3. The previous difficulty has been the lack of any biological system allowing an in vivo assessment that differentiates the role of class Ib from Ia molecules. The availability of H2-Db, Kb double-KO mice allowed Seaman and co-workers (1999) to pinpoint a role for H2–M3 for immune response against Listeria monocytogenes.

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The MICA gene was initially sequenced from 92 homozygous typing cell lines collected during the course of the 10th International Histocompatibility Workshop (Bahram et al., 1994; Fodil et al., 1996, 1999). Nucleotide sequence determination of exons 2, 3, and 4 was performed either by sequencing of cloned PCR fragments or by direct sequencing of PCRamplified material. In conjunction with data reported by other investigators (Petersdorf et al., 1999; Visser et al., 1999; Yao et al., 1999), 54 MICA alleles have been identified to date, among which 47 encode distinct putative glycoproteins (Fig. 6 and Tables III and IV) (for the current status, the reader is referred to http://mhc-x.u-strasbg.fr). These are defined by a total of 40 nucleotide substitutions, 30 of which are nonsynonymous: 5 of 8 in 움1, 15 of 16 in 움2, and 10 of 16 in 움3 (Fodil et al., 1999) (Tables III and IV). Resembling classical HLA class I molecules, MICA polymorphic residues are slightly more prevalent in the 움2 domain (Fodil et al., 1996); however, in contrast to classical class I molecules, MICA seem equally diverse within the 움3 domain. MHC-Ia polymorphic residues are concentrated within the antigen-binding cleft in contact with the peptide or the TCR (Bjorkman and Parham, 1990). Moreover, the majority of nucleotide changes in this cleft are nonsynonymous (Hughes and Nei, 1988), creating a strong case for overdominant selection as (mostly likely) exerted by infectious agents in maintaining MHC alleles (Hill, 1998; Klein and O’Huigin, 1994; Parham and Ohta, 1996). In this context, the nature of selective forces maintaining MIC polymorphism is an open question; interestingly, an overwhelming majority of nucleotide variations in the MICA putative antigen-binding cleft give rise to nonconservative amino acid substitutions, whereas the opposite trend is seen in the Ig-like 움3 domain. Among the amino acid substitutions, several are drastic in nature and may have radical effects in putative ligand/ receptor binding. These are predominantly in the 움1 and 움2 domains and include R6P, Q91R, G114R, K125E, H156L, K173E, T181R, W210R, and Q251R. In contrast, six of eight changes in the 움3 domain are conservative, and among these, three are shared by at least one human or murine class I molecule (Bahram et al., 1994; Fodil et al., 1996) (Fig. 6 and Table III). These latter include G206S, T213I, and S215T. It is remarkable that almost none of the MICA variable residues coincide with the polymorphic positions of MHC-I molecules, which are mainly residues in direct contact with the peptide or the TCR, located in the 움1 domain–encoded 움-helices and the 움2 domain–encoded 움-strands (Bjorkman and Parham, 1990; Fodil et al., 1996; Madden, 1995). It is also noteworthy that nine of the MICA variable residues are located precisely at the positions at which MICA and MICB sequences differ, and indeed, eight of these are identical to MICB residues at these positions: T24A, C36Y, K125Q, M129V, G206S, W210R, S215T, and S268G

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(Bahram and Spies, 1996; Fodil et al., 1996). This implicates intergenic conversion events as a mechanism for the establishment of MICA polymorphism, as has been the case for other HLA molecules (Parham and Ohta, 1996). Finally, computation of the allelic variation within the three extracellular domains of 움1–움3 led to an average heterozygosity per nucleotide site (nucleotide diversity) of 0.011. [this analysis is based on the thenknown MICA001–016 alleles (Fodil et al., 1996)] This is remarkably close to that of the antigen-presenting class Ia loci (0.04–0.08) and drastically higher than that (0.0002–0.007) for other nuclear genes (Nei et al., 1997), strongly favoring overdominant selection as the mechanism for maintenance of MIC alleles. Plotting the MICA 움1움2-located variable residues on Li and colleagues’ crystal structure generates a footprint remarkably similar to that of initial simulations (Fig. 5). During the course of genomic sequencing of the MICA locus, a peculiar allelic diversity was uncovered within the transmembrane exon (Mizuki et al., 1997). This exon harbors a multiallelic STR, where a variable number of GCT repeats encode 4, 5, 6, 9, and 10 A residues, respectively, and are therefore called A4, A5, A6, A9 (Mizuki et al., 1997), and A10 (PerezRodriguez et al., 2000). Curiously, no A7 or A8 repeats have been encountered to date, which is surprising given the fact that most STRs have evolved by sequential addition of single repetitive units. Finally, certain MICA alleles carry a nucleotide insertion (GCT 씮 GGCT) causing a frameshift mutation resulting in a premature stop codon within the transmembrane segment (Mizuki et al., 1997). These alleles give rise to a truncated glycoprotein of 35–40 kDa (M. Colonna and S. Bahram, unpublished observations) which eventually reaches the cell surface (albeit at a presumably nonphysiological site; see below for details) and hence might not be secreted as was originally thought. This 5.1 STR defines the transmembrane segment of MICA008 allele (see below), the most frequent MICA allele in several populations examined so far (Fodil et al., 1999). Given the very short distance separating MICA from HLA-B, a vigorous degree of positive linkage disequilibrium is expected. Examples are association of HLA-B*0702 and HLA-B*0801 with MICA008/5.1 (the latter defines the MICA allele within the conserved haplotype HLA-A*0101, B*0801, DRB1*0301), HLA-B*1402 with MICA011/6, HLA-B*27052 with

FIG. 6. MICA alleles. Domain-by-domain multiple alignment of the presently available MICA alleles. Only 47 (of 54) alleles defined by distinct amino acid sequences are shown. For full nucleotide data, see Table IV. For updates, see http://mhc-x.u-strasbg.fr. Dashes define positions identical to those of the MICA001 allele. Transmembrane (TM) sequences report only the short tandem repeat.

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FIG. 6. (Continued )

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34

FIG. 6. (Continued )

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TABLE III MICA NUCLEOTIDE VARIATION Positions Exon 2 6 14 23 24 26 36 56 64 Exon 3 91 105 112 114 122 124 125 129 142 151 156 156 173 175 176 181 Exon 4 191 193 198 205 206 210 213 215 221 247 251 251 255 256 268 271 Exon 5 293 295

Codon

(␣1) (5 of 8)

(␣2) (15 of 16)

(␣3) (10 of 16)

Amino Acid

CGT TGG CTC ACT GTA TGT AAT AGA

씮 씮 씮 씮 씮 씮 씮 씮

CCT GGG CTT GCT GGA TAT AAC AGG

Arg Trp Leu Thr Val Cys Asn Arg

씮 씮 씮 씮 씮 씮 씮 씮

Pro Gly Leu Ala Gly Tyr Asn Arg

CAG AGG TAC GGG CTG ACT AAG ATG GTC ATG CAC CAC AAA GGC GTA ACA

씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮

CGG AAG TAT CGG GTG TCT GAG GTG ATC GTG CTC CGC GAA AGC ATA AGA

Gln Arg Tyr Gly Leu Thr Lys Met Val Met His His Lys Gly Val Thr

씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮

Arg Lys Tyr Arg Val Ser Glu Val Ile Val Leu Arg Glu Ser Ile Arg

AGC GCC ATT TCT GGC TGG ACA AGC GTA ACC CAA CAA CAG AGG AGC CCT

씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮

AGT GCA ATC TCC AGC CGG ATA ACC CTA ACT GAA CGA CAA AGT GGC GCT

Ser Ala Ile Ser Gly Trp Thr Ser Val Thr Gln Gln Gln Arg Ser Pro

씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮 씮

Ser Ala Ile Ser Ser Arg Ile Thr Leu Thr Glu Arg Gln Ser Gly Ala

(transmembrane) (GCT)4,5,6,9,10 GCT 씮 GGCT

(Ala)4,5,6,9,10 (Ala)2 –stop at 310

Positions refer to amino acid residues. Numbers in parentheses correspond to the ratio of nonsynonymous to total substitutions.

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TABLE IV AVAILABLE HUMAN MICA ALLELES Allelea MICA001 MICA002 MICA004 MICA005 MICA006 MICA007 MICA008 MICA009 MICA010 MICA011 MICA012 MICA013 MICA014 MICA015 MICA016 MICA017 MICA018 MICA019 MICA020 MICA021 MICA022 MICA023 MICA024 MICA025 MICA026 MICA027 MICA028 MICA029 MICA030 MICA031 MICA032 MICA033 MICA034 MICA035 MICA036 MICA037 MICA038 MICA039 MICA040 MICA041 MICA042 MICA043 MICA044 MICA045

Previous Name

Accession

MUC17 MUC21 MUC22 MUC24 MUC25 MUC26 MUC28 MUC29 MUC30 MUC31 MUC32 MUC33 MUC34 MUC35 MUC36 MICAKWHT MICAAIB MICAAKB MICAALAB MICABCC MICABEA MICABEE MICABHB MICACEA MICACEC

U56940 U56941 U56943 U56944 U56945 U56946 U56947 U56948 U56949 U56950 U56951 U56952 U56953 U56954 U56955 AF097403 AF097404 AF097405 AF097406 Y18110 Y16804 Y16805 Y16807 Y16808 Y16809 Y16811 Y18111 Y18112 Y18113 Y18114 Y18115 Y18116 Y18117 Y18118 AH006333 AH007170 AH007171 AH007172 AH007173 AH007174 AH007182 AH007176 AH007177 AH007178

Reference Bahram et al. (1994) Bahram et al. (1994) Bahram et al. (1994) Bahram et al. (1994) Fodil et al. (1996) Fodil et al. (1996) Fodil et al. (1996) Fodil et al. (1996) Fodil et al. (1996) Fodil et al. (1996) Fodil et al. (1996) Fodil et al. (1996) Fodil et al. (1996) Fodil et al. (1996) Fodil et al. (1996) Fodil et al. (1999) Fodil et al. (1999) Fodil et al. (1999) Fodil et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Yao et al. (1999) Petersdorf et al. (1999) Visser et al. (1999) Visser et al. (1999) Visser et al. (1999) Visser et al. (1999) Visser et al. (1999) Visser et al. (1999) Visser et al. (1999) Visser et al. (1999) Visser et al. (1999) (continues)

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TABLE IV Continued Allelea

Previous Name

Accession

MICA046 MICA047 MICA048 MICA049 MICA050 MICA051 MICA052 MICA053 MICA054

MICACEF MICACIB HSMICGG HSMICGGA HSMICGGB HSMICGGC HSMICGGD HSMICGGE HSMICGGG

AH007179 AH007180 AH007472 AH007473 AH007474 AH007475 AH007476 AH007477 AH007479

Reference Visser et al. (1999) Visser et al. (1999) Y. Mitsuishi et al. (unpublished Y. Mitsuishi et al. (unpublished Y. Mitsuishi et al. (unpublished Y. Mitsuishi et al. (unpublished Y. Mitsuishi et al. (unpublished Y. Mitsuishi et al. (unpublished Y. Mitsuishi et al. (unpublished

observations) observations) observations) observations) observations) observations) observations)

a Alleles are numbered in order of their respective identification. Allele MICA003 has been deleted, as it has not been found in subsequent sequencing efforts.

MICA007/4, HLA-B*4001 with A008/5.1, and finally HLA-B*4402 with MICA008/5.1 (Fodil et al., 1999). Exceptions subsist, however; for example, the most common MICA allele, MICA008/5.1, is variously linked to HLAB*0702, HLA-B*0801, HLA-B*1302, HLA-B*4001, HLA-B*4402, and HLA-B*4701. Several medium-sized population studies allowed an initial assessment of the distribution pattern of MICA alleles within various populations (Fodil et al., 1999; Petersdorf et al., 1999). The gathered information clearly reveals that MICA008, as already mentioned, is the most frequent allele, possibly at the worldwide level. Following are a myriad of other alleles, the most prominent of which are MICA002, -004, or -010, although the distribution of these shows a high degree of interethnic variability. The MICA008 allele is unique in that it carries, almost invariably, the 5.1 transmembrane sequence defined by a shortened transmembrane segment, and consequently has no cytoplasmic tail, giving rise to a diminished 38to 40-kDa glycoprotein (M. Colonna et al., unpublished observations) with an apparent faulty subcellular localization (Suemizu et al., unpublished data). MICB seems to be less diverse than MICA, although this has been less thoroughly explored. Presently, 16 MICB alleles have been documented, among which 13 differ by protein sequence (Fig. 7 and Tables V and VI). MICB alleles are defined by a total of 15 nucleotide substitutions (within

FIG. 7. MICB alleles. Domain-by-domain multiple alignment of the presently available MICB alleles. Only 11 (of 14) alleles with distinct amino acid sequences are shown. For full nucleotide data, see Table VI. For updates, see http://mhc-x.u-strasbg.fr. Dashes define positions identical to those of the MICB001 allele. The MICB010 allele carries a nonsense mutation in the 움2 domain.

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TABLE V MICB NUCLEOTIDE VARIATION Position Exon 2 16 45 52 57 82 Exon 3 98 113 170 Exon 4 189 192 210 243 256 267 268 Exon 5 277

Codon

(␣1) (5 of 5)

(␣2) (3 of 3)

(␣3) (4 of 7)

(transmembrane)

GAA CCC GAT AAG GAC

씮 씮 씮 씮 씮

GGA CAC AAT GAG GGC

Amino Acid Glu Pro Asp Lys Asp

씮 씮 씮 씮 씮

Gly His Asn Glu Gly

ATC 씮 ATG GAT 씮 AAT CGA 씮 TGA

Ile 씮 Met Asp 씮 Asn Arg 씮 Stop

ACC 씮 GAG 씮 CGG 씮 ACC 씮 AGG 씮 CAC 씮 GGC 씮

Thr Glu Arg Thr Arg His Gly

ATC AAG CGA ACG AAG CAT AGC

GCG 씮 GTG

씮 씮 씮 씮 씮 씮 씮

Ile Lys Arg Thr Lys His Ser

Ala 씮 Val

Positions refer to amino acid residues. Numbers in parentheses correspond to the ratio of nonsynonymous to total substitutions.

the extracellular region), 12 of which are nonsynonymous: 5 of 5 (nonsynonymous versus total), 3 of 3, 4 of 7, respectively, in the 움1, 움2, and 움3 domains (Table V) (Ando et al., 1997; Bahram and Spies, 1996; Fischer et al., 2000; Pellet et al., 1997; Visser et al., 1998). Possibly the most interesting aspect of MICB diversity was the report by Ando and colleagues (1997) of a MICB null allele. This allele, MICB010 (also called MICB0107N ), carries a stop codon within the 움2 domain (Table V). Interestingly, this allele is invariably linked to a 100-kb genomic deletion, including the more telomeric MICA gene. This peculiar haplotype is described in detail below. Finally, the presence of a long, 1000-fold TA-repeat microsatellite between MICA and MICB is of interest, as it might represent a potential hot spot for recombination (Ando et al., 1997), although our knowledge of the extent of positive or negative linkage disequilibrium between MICA and MICB alleles is still fragmentary. 2. Disease Susceptibility In this fast-paced genomic era in which few weeks go by without the molecular resolution of a mendelian disorder or a genome-wide scan in

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TABLE VI AVAILABLE HUMAN MICB ALLELES Allele

Previous Name

Accession

Reference

MICB001 MICB002 MICB003 MICB004 MICB005 MICB006 MICB007 MICB008 MICB009 MICB010 MICB011 MICB012 MICB013 MICB014 MICB015 MICB016

— MICB01021 MICB01022 MICB01023 MICB0103101 MICB0103103 MICB0104 MICB0106 MICB0105 MICB0107N — — — — MICB01022v MICB013101v

X91625 SEG AB003599s SEG AB003600s SEG AB003601s SEG AB003602s SEG AB003604s SEG AB003605s SEG AB003607s SEG AB003606s SEG AB003608s AF021225 AF021226 U95732 U95731 — —

Bahram and Spies (1996) Ando et al. (1997) Ando et al. (1997) Ando et al. (1997) Ando et al. (1997) Ando et al. (1997) Ando et al. (1997) Ando et al. (1997) Ando et al. (1997) Ando et al. (1997) Visser et al. (1998) Visser et al. (1998) Pellet et al. (1997) Pellet et al. (1997) Fischer et al. (2000) Fischer et al. (2000)

search for causative loci behind the so-designated ‘‘complex diseases,’’ it is surprising, if not frustrating, to see how a rather minute segment of the human genome, the HLA complex (3.8 Mb;
 of the genome), has remained such a formidable genetic puzzle. Nevertheless, the situation is fairly simple. Through the work of a large number of investigators during the past 30 years, we now have a collection of over 100 diseases associated to varying degrees with HLA alleles (Bodmer, 1980; Charron, 1997; Dausset and Svejgaard, 1977). These range from a fairly moderate association of Hodgkin’s lymphoma (which incidentally was the first such disease recognized) with HLA-DPB1*0301 (for a review, see Amiel, 1971) to the near-absolute association of ankylosing spondylitis with HLA-B27 (Brewerton et al., 1973; Schlosstein et al., 1973) as well as narcolepsy with HLADQB1*0602/DQA1*0102 ( Juji et al., 1984; Langdon et al., 1984). Falling between these extremes are most other HLA-linked pathologies. These embrace the linkage of rheumatoid arthritis to HLA-DRB1*0401 (Stastny, 1978), multiple sclerosis with HLA-DR2 (DRB1*1501) (de Moerloose et al., 1979), type I diabetes with DQB1*0302 (Todd et al., 1987; Yunis et al., 1976), systemic lupus erythematosus with HLA-DR2/DR3 alleles (Walport et al., 1982) or complement deficiency (Hauptmann et al., 1974), and IgA deficiency with the conserved HLA-A1, B8, DR3 haplotype (Strothman et al., 1986). Except in two circumstances—association of adrenal hyperplasia with complement genes (Pollack et al., 1981) and hereditary hemochromatosis with HLA-A3, -B14 haplotypes (Simon et al., 1976)

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[which were eventually linked to 21-OH and HFE genes respectively (White et al., 1984; Feder et al., 1996)]—the molecular impetus behind most of these diseases remains unknown.28 The major hurdle hindering the advance in this field is the formidable linkage disequilibrium across the entire MHC, precluding, in most cases, the incrimination of single loci (Ceppellini, 1976). In the array of MHC-associated diseases, several tissue-specific disorders linked specifically to the class I region have unique characteristics. (i) Unlike most MHC-associated diseases, including, for example, type I diabetes, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, they are not associated with a MHC haplotype (where MHC-II alleles are usually predominant) but solely with certain MHC-I alleles. (ii) They show a coherent pattern of tissue disturbance, affecting, to various degrees, epithelial/endothelial/conjunctive tissues (i.e., skin, gut, joints, and the eyes), suggesting the existence of an anatomically restricted pathogenic element acting independently or in conjunction with the ubiquitously expressed MHC-I molecules. (iii) They affect young males in their second or third decade, unlike typical MHC-linked autoimmune disorders affecting women in their mid-30s and 40s. These include the well-known associations of seronegative spondyloarthropathies with the HLA-B27 gene (Brewerton et al., 1973; Schlosstein et al., 1973), the association of psoriasis vulgaris with HLA-Cw6 (Oka et al., 1999; Ozawa et al., 1979), and finally the linkage of the Behc¸ et’s disease and HLA-B51 (Ohno et al., 1978). Although it is thought that HLA molecules play a direct role in the etiopathogenesis of these syndromes, most likely via presentation of ‘‘deleterious’’ peptides, to date no direct evidence substantiates this assumption. The high degree of linkage disequilibrium between MICA alleles and those of the closely linked HLA-B gene as well as the unique pattern of MICA tissue expression are sufficient reasons for us to consider MICA as a candidate gene in the disorders mentioned above. A small number of HLA-linked diseases have been examined so far for their potential linkage with MICA alleles, mainly selected on the basis of their known pathophysiology. A preliminary as well as a more thorough investigation of the MICA TM-STR allele did not demonstrate any primary linkage with ankylosing spondylitis (Goto et al., 1997; Yabuki et al., 1999). 28 The most plausible scenario linking HLA alleles to autoimmune disorders is that of ‘‘faulty’’ peptide sampling to T cells, that is, presentation of tissue-specific self antigens not encountered in the course of T cell maturation within the thymus. However, very simple questions remain unanswered. For example, regarding HLA-B27–linked spondylarthropathies, why is it that only a few percent of B27-positive individuals develop the disease (given the fact that B27 seems to be the unique or the most prominent genetic susceptibility element)?

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A satellite disorder of this condition, acute anterior uveitis, did show, however, a more pronounced linkage with the MICA TM-STR A4 allele; however, this requires confirmation on a larger panel as well as investigation of extracellular variants (Goto et al., 1998a,b). Investigation of Behc¸ et’s disease provided the first interesting link between MICA alleles and an HLA-B linked disorder in the Japanese population. Indeed, the MICA TMSTR A6 and MICA009 alleles are significantly linked to Behc¸ et’s disease in several ethnically distinct populations (French, Greek, Iranian, Italian, Japanese, Lebanese, and North African). However, there is a very strong link between HLA-B51 and MICA009 itself, and the strength of this association appears to swing from one locus to the other based on the examined population. It is possible that both of these molecules contribute to the genetics of this complex disorder (Mizuki et al., 1997, 1999; Wallace et al., 1999). Although HLA-Cw6–linked psoriasis does not show any noticeable association with MICA alleles (Oka et al., 1999), psoriatic arthritis apparently displays a specific linkage with MICA A9 STR (linked mainly with the MICA002 allele) independent of HLA-C association (Gonzalez et al., 1999). Finally, two of the MHC-II (or pan-MHC)–linked disorders— multiple sclerosis and celiac disease—do not appear to show any primary linkage to MICA (N. Fodil, M.-P. Roth, and S. Caillat, unpublished observations). 3. Histocompatibility Little (1914) along with Tyzzer (1909), and later Snell (1948), truly initiated the field of transplantation immunogenetics, within the first half of the 1900s.22 A number of seminal experiments, consisting mainly of tissue and tumor grafting between genetically homogenous and, later, inbred strains of mice, led to the identification of the so-designated ‘‘major’’ histocompatibility complex among a large number of histocompatibility loci (H2 was a member of H1–H14).29 To date, the single most important contribution of the MHC in day-to-day clinical practice is to help ensure near-tissue compatibility between donor and recipients of organ and tissue 29 In order to grasp the route to MHC discovery, one must go back to the turn of the 20th century, when Cue´ not and Mercier were probably the first scientists to tackle the problem of tumor genetics. Despite their defeat in finding any correlation between coat color and tumor susceptibility, they possibly prepared the way for others’ successful experiments. These came from Loeb (1909), along with Tyzzer in conjunction with his Ph.D. student, Little, who incidentally later, in 1929, founded the Jackson laboratory, where other crucial experiments were about to happen. These were mainly carried out by Snell and in part in collaboration with Gorer, a British scientist on sabbatical leave (Tyzzer, 1909; Little, 1914). This enormous genetic undertaking within the first half of the 20th century clearly paved the way for the understanding of histocompatibility molecules, which were also greatly boosted through the identification of their human counterparts (Dausset, 1958).

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grafts. Although HLA alleles clearly affect the long-term survival rate of kidney transplant recipients, solid organ transplantation in general does not show as critical a reliance on MHC compatibility as does hematopoietic stem cell transplantation [hereafter referred to as bone marrow transplantation (BMT)] (Sasazuki et al., 1998). Several large-scale retrospective analyses have demonstrated an incremental increase in posttransplant complications (mainly the life-threatening graft-versus-host disease) corresponding to the degree of incompatibility between donor and recipients (Sasazuki et al., 1998). Within the framework of allogeneic BMT, clinical results are substantially better when the donor is a haplotype-matched family member rather than an HLA-compatible, unrelated individual (Anasetti et al., 1995; Charron, 1996). At least part of this discordance may reside in yet unidentified polymorphic loci within the MHC. For a number of reasons, MICs are obvious candidates as histocompatibility loci; these include their structure, their unusual degree of polymorphism, and their epithelial pattern of expression (which parallels the complex pathological spectrum of the graft-versus-host disease). The task is complicated, however, given the absence of any murine orthologue or obvious functional equivalent.30 So we are left with the human system, in which retrospective analysis of the increasingly large numbers of unrelated donor BMTs should help decipher the role (if any) of MICA in histocompatibility. Complete sequence analysis of the MICA gene within a large set of complete haplotype-matched unrelated donor BMTs revealed an almost absolute degree of identity between donor and recipients, although a few authentic mismatches existed (B. Cuillerier and M. Ota, unpublished observations). This work may indicate that perhaps MIC typing would not be of additional diagnostic value compared to routinely used HLA typing, but it does not have the power to assess the role of MIC genes as transplantation antigens. To explore this avenue, one may have to analyze an even larger panel of mismatched HLA-B allele grafts and to independently analyze the putative contribution of MICA and eventually MICB by multivariate analysis. B. MICAB⫺/⫺ INDIVIDUALS The study of genetically deficient individuals has taught us a great deal about how the immune system functions in the ‘‘real world.’’ The most notable examples are challenges of immunodeficiency due to the absence of MHC-II or -I molecules (Frelinger and Serody, 1998; Grusby and Glimcher, 1995; Mach et al., 1996). Most of these human disorders have been elegantly paralleled by murine models in which the same genes were 30 Although this issue could be addressed once transgenic mice strains expressing diverse MICA and MICB alleles are investigated as to grafting.

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abrogated by homologous recombination. Obviously, the latter permits direct experimentation and exposure to a well-controlled pathogenic (infectious) environment. As previously mentioned, upon their discovery, it was obvious the rodents were probably the only mammals devoid of MIC genes (Bahram et al., 1994). Hence, we were left in search of elusive human subjects deleted not only for MICA but also for MICB. Watanabe and colleagues (1997) were the first to allude to a large (앑100 kb) deletion within the HLA class I region based on pulsed-field gel electrophoresis experiments. Tokunaga and co-workers were able to further delineate the boundaries of this deletion and made the remarkable discovery that some of these HLA-B*4801– carrying haplotypes have expunged a 100-kb DNA segment including the MICA gene (Komatsu-Wakui et al., 1999). This, combined with the previous report by Ando and co-workers (1997) of a MICB null allele within precisely the same haplotype, made it clear that a fraction of HLA-B*4801 chromosomes are MICA–MICB compound knock-outs (present estimates on a limited number of cases suggest that slightly over half of the HLAB*4801 haplotypes are MIC null). Given the 3.2% frequency of the HLAB*4801 within the Japanese population, a 0.1024% homozygous carriage is expected. So far, and based on a very limited number of cases, 62.5% (5 of 8) of these haplotypes carry the MIC null configuration; hence, given the actual size of the Japanese population, over 80,000 individuals (80,640 based on a population of 126 million) in Japan alone carry this haplotype at homozygosity: MICB*0107N, MICA⫺, HLA-B*4801. The HLA-B*4801 is extremely rare outside of Southeast Asia, with the exception of the Amerindian populations. As the first examined MIC⫺/⫺ individuals were blood donors, ‘‘MIC deficiency’’ apparently does not lead to any manifest clinical symptoms, in clear contrast to the mild to severe immunodeficiencies consequent to the absence of MHC-I or -II molecules. These homozygous individuals (MICAB⫺/⫺) are therefore crucial to dissecting the in vivo role of the MIC genes. These individuals are apparently indistinguishable with respect to other blood donors upon routine clinical examinations. Moreover, an extensive phenotype analysis of various B, T, and NK lymphocyte subpopulations from a limited number of these individuals did not reveal any anomalies. In particular, the number of B (CD19⫹, CD21⫹ ), 움/웁 TCR⫹ (CD4⫹ and CD8⫹ ), 웂/␦ TCR⫹, including V␦1 subpopulations, and, finally NK (CD16⫹, CD56⫹, KIR⫹ ) were present in proportions comparable to those in ‘‘normal’’ (undeleted) HLA-B48–carrying individuals (M. Cella, N. Fodil, M. Ota, H. Inoko, M. Colonna, and S. Bahram, unpublished observations). It might also be worthwhile to consider the fact that even within the HLAB48 haplotypes with an intact MICA gene, most contain the 008 or 010

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allele (Katsuyama et al., 1999). The MICB allele carried by the intact HLAB4801 haplotype is MICB002 (MICB0102, according to Ando et al., 1997) (Ota et al., 2000). MICA008, as previously mentioned, is unique in that it carries a shortened transmembrane segment and displays an aberrant membrane localization; as to allele MICA010, it alone carries a nonconservative amino acid substitution at the beginning of the 움1 domain, R6P (Fodil et al., 1996), which hinders surface expression (Li et al., 2000). Finally, it seems obvious that a more detailed study of the immune system in these individuals, especially with respect to 웂/␦ and NK lymphocyte function, will provide invaluable data with regard to MIC immunobiology. VI. Conclusion

All things considered, MIC genes have mainly added to the confusion dominating the puzzling field of non–peptide-binding MHC-I genes. Present knowledge, especially regarding the absence of these genes in mice as well as their apparent dispensability in humans, suggests that they do not perform functions as fundamental as those ascribed to innate elements of the immune system (Diefenbach and Raulet, 1999). This raises the question as to their true utility to the immune system.31 In this respect, two opposite conclusions could be drawn: either MIC genes have arisen to specifically defend epithelial cells against aggressors, foreign (microbes) or domestic (neoplastic transformation), or they have collected a number of characteristics common to the whole family of histocompatibility molecules (e.g., polymorphism, stress induction, or TCR reactivity). Hence, they may be yet another gene family that has flourished and yet is about to vanish, as this is supposedly the fate of most class I gene families, including the most prominent one, the HLA loci. Although the first hypothesis is in line with today’s conventional immunological school of thoughts, the second is best adapted to a darwinian view of the defense organization, which would stipulate that successive waves of microbiological offensives have constantly remolded the MHC genomics. As often, the truth might reside between the two extremes. This is not an esoteric issue, as it might help resolve outstanding questions that have been stalking the class I loci since their very identification. Among many questions that must be answered regarding MIC genes, perhaps two are most fascinating. First, what is the origin of this second set of class I genes within the MHC itself ?23 Second, what is the driving force behind this peculiar, rather disconcerting pattern of polymorphism? An answer to the first question has been elegantly 31 This question is not limited only to MICs as it applies to almost every MHC-Ib molecule so far identified, even the ones where a function in host defense has been clearly documented (Bouwer et al., 1994; Lo et al., 2000; Pamer et al., 1992; Seaman et al., 1999).

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provided by the genomic work of Shiina et al. (1999), which allows us to trace the origin of MICs to the roots of the human class I region; the answer to the second question is still in the making (Fodil et al., 1996, 1999). The mystery of these genes may be solved once the more general question of why vertebrates utilize a common structure, the MHC-I–fold, in such unrelated functions ranging from iron homeostasis to IgG transport, is answered; in other words, why has the MHC served as a training ground of sorts for nature’s experimentation with such complex structures? In fine, and within the near future, the MIC world should remain focused on the breadth of MICA/B engagement in 웂/␦ and NK biology, the in vivo significance of their stress induction in both anti-infectious and antitumor responses, and the involvement of their diversity in different pathologies as well as solid and marrow organ transplantations. ACKNOWLEDGMENTS I thank Susan Gilfillan, Marco Colonna, and Marc Bonneville for comments on the manuscript; Hidetoshi Inoko for many insightful discussions; as well as Georges Hauptmann and Fritz Melchers for longstanding encouragement and support. Research in our laboratory was performed by Benoıˆt Cuillerier (who compiled the data presented in Figs. 4–6 and 7 as well as in Tables II, IV, and VI), Nassima Fodil, Mirjana Radosavljevic, Vale´ rie Wanner, and Sophie Wicker. Support is acknowledged from the Action Concerte´ e Incitative Jeunes Chercheurs du Ministe`re de l’E´ ducation Nationale, de la Recherche et de la Technologie; the Fondation pour la Recherche Me´ dicale—Action Recherche Sante´ 2000; the Ligues De´ partementales (67–68) Contre le Cancer; and the Association pour la Recherche sur le Cancer.

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