On the origins of adaptive immunity: innate immune receptors join the tale

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On the origins of adaptive immunity: innate immune receptors join the tale Timo K. van den Berg1, Jeffrey A. Yoder2,3,4 and Gary W. Litman3,4 1

Department of Molecular Cell Biology, VU Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands Department of Biology, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA 3 Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Avenue, Tampa, FL 33612, USA 4 Department of Pediatrics, University of South Florida College of Medicine, All Children’s Hospital, St Petersburg, FL 33701, USA 2

Among members of the Ig superfamily (IgSF), antigen receptors have the unique capacity to rearrange their variable domains, thereby creating an extensive repertoire for antigen recognition. It is assumed that antigen receptors evolved from a non-rearranging IgSF member by insertion of a transposable element. Although the nature of this predecessor is unknown, two multigene families of innate immune receptors that bear a close structural resemblance to antigen receptor chains have been identified in mammals and bony fish, respectively: signal-regulatory proteins (SIRPs) and novel immunetype receptors (NITRs). Members of both families encode V-set Ig domains with a typical antigen receptor-like joining (J) motif and possess the potential to signal through immunoreceptor tyrosine-based inhibition motifs (ITIMs) or immunoreceptor tyrosine-based activation motifs (ITAMs). By analogy to the T-cell receptor (TCR) and certain innate receptors [e.g. killer cell inhibitory receptors (KIRs)] that recognize MHC molecules, SIRP members regulate immune function by interaction with broadly expressed ‘self’ ligands. We propose the existence of an evolutionary and functional link between innate and adaptive immune receptors that sheds light on the nature of the antigen receptor predecessor(s). The vertebrate adaptive immune system has evolved to recognize and respond to an extraordinary range of antigens. Antigen recognition is mediated by T-cell antigen receptors (TCRs) and immunoglobulin (Ig) B-cell receptors (BCRs), which are expressed clonally on the surface of lymphocytes, and an extensive repertoire of these antigen receptors is available in the body [1]. TCRs and Igs have been identified in all major phylogenetic groups of jawed vertebrates, but not in jawless vertebrates or invertebrates [2,3]. Antigen receptors are composed of two antigen recognition chains: the a and b, or g and d, chains in TCRs; and the heavy (H) and light (L) chains in Ig BCRs. These associate with CD3 (TCR) or CD79 (BCR) chains, which mediate signaling (Figure 1). The extracellular portion of each of the antigen recognition chains is composed of Ig-like domains, of which the membrane-distal variable (V)-set Ig domain is Corresponding author: Timo K. van den Berg ([email protected]).

responsible for antigen recognition, whereas the constant domains mediate effector functions [1]. Within the V domains, three hypervariable loops called the complementarity-determining regions (CDRs) contribute to antigen recognition. Diversity in CDR1 and 2 is encoded by the germline, whereas that of CDR3 is established (somatically) by the joining of encoded V-, diversity (D)- and joining (J)-gene segments. As V-, D- and J-gene segments are selected from a considerable number of variant genomic sequences, this process of somatic rearrangement generates an enormous potential for diversity. In addition, joining is imprecise and this further expands the repertoire significantly. Importantly, somatic rearrangement is unique to TCRs and Igs. It seems probable that all antigen receptor chains descended from a common, rearranging antigen receptor that existed before the branching of fish and tetrapods some 500 million years ago [2,3]. The question is: how did this highly specialized system evolve? Antigen receptors probably evolved from a primordial, non-rearranging IgSF molecule with a J-like segment It is clear that Ig-like domains are found not only in antigen receptors, but constitute the basic building block of a much larger family of molecules: the immunoglobulin superfamily (IgSF) [4]. In fact, approximately a third of the cell-surface receptors expressed on leukocytes are IgSF members [5]. Furthermore, the majority of IgSF members are cell-surface molecules and their extracellular Ig domains generally mediate recognition, often of cellsurface ligands. On the basis of length and structural properties, four major types of Ig domains can be distinguished: V-, C1-, C2- and I-set domains [4,6]. Most IgSF members identified to date carry I and/or C2 domains. The fact that IgSF members are present in invertebrates clearly shows that the Ig domain has been in existence long before the rearranging antigen receptors evolved [7,8]. The crucial difference between antigen receptors and other IgSF members with V regions is that the former have V-set Ig domains built from separate genomic V, (D) and J segments, whereas the latter have Ig domains that are usually encoded within a single exon [4]. Another typical feature of the rearranging antigen receptors is that their constant domains are of the C1-type, and these have thus far been found only in a few non-rearranging IgSF

http://treimm.trends.com 1471-4906/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2003.11.006

Opinion

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BCR

Vol.25 No.1 January 2004

IgL

VJ*

VJ* C1

C1

IgH

VJ*

SIRPβ1 SIRPα

VJ* C1

CD79b CD79a

C1

C1

C1

CD3γ CD3δ VJ*

C1

VJ* CD3ε

C1

C1

VJ

VJ

C1

C1

C1

VC2J

VC2J

β

C2

DAP12

VJ' VJ' CBD

ITIM

CD3ζ

NITR

ITAM

C2

VJ

ITIM

C2

VCBP

VJ

ITAM

ITAM

C1

α

TCR

ITAM

ITAM

C1

ITAM ITAM

C2

C1

ITAM

VJ

C1

ADAPTOR?

ILT

Siglec

KIR

C2

C2

C2

C2

FcR C2

C2

C2

C2

C2

C2

C2

C2

C2

ITIM

ITIM

DAP12

γ-chain

ITAM

C2

ITIM

C2

ITAM

C2

ITIM

C2

ITAM

V

γ-chain TRENDS in Immunology

Figure 1. View of rearranging receptor families (BCRs and TCRs) and representative members of different non-rearranging immune receptor families. Note that most innate immune receptor families illustrated encode both activating and inhibiting receptors. Abbreviations: BCR, B-cell receptor; C1, C1-set Ig domain; C2, C2-set Ig domain; CBD, chitin-binding domain; ILT, Ig-like transcript; ITAM, immunoreceptor tyrosine-based activation motif (white boxes); ITIM, immunoreceptor tyrosine-based inhibition motif (orange boxes); KIR, killer-cell inhibitory receptor; TCR, T-cell receptor; V, V-set Ig domain; VC2J, mixed V/C2 Ig domain containing J-like sequence; VCBP, V region-containing chitin-binding protein; VJ, V-set Ig domain containing J-like sequence; VJp, rearranging VJ-domain; VJ0 , VJ domain with a partial J-sequence.

molecules (e.g. MHC). It therefore seems highly probable that antigen receptors evolved from a primordial nonrearranging IgSF molecule and that the insertion of a RAG-dependent transposable element between the V(D) and J segments formed a key step in the development of somatic rearrangement [9]. What did the molecule that formed the target for this crucial transposition event look like and what were its functions? The C-terminal part of the J segments of antigen receptor V domains, which forms the so-called framework region 4 that flanks CDR3, contains a characteristic conserved sequence motif: (F)GXGTXLXV [10]. It seems reasonable to assume that such J-like sequences were also present in the putative antigen receptor predecessor and that descendents of this molecule might still be surviving along with antigen receptors in jawed vertebrates. Indeed, J-like sequence motifs are found in several non-rearranging receptors that contain a single V-set extracellular domain (Table 1), including CD8b, CD79b, CD7, NKp30, ChT1 [CTX (cortical thymocyte-specific antigen of Xenopus)] and the DORA (downregulated by activation) protein. In each of these cases, the J-like sequence is encoded within the V exon. The members of two recently identified multigene families – the signal-regulatory proteins (SIRPs) and the novel immune-type receptors (NITRs) – show even closer relationships to antigen receptors, because they possess a joined VJ segment (i.e. encoded within the same exon) combined with constant Ig-like domains. Interestingly, most SIRP and NITR family members exhibit http://treimm.trends.com

potential signaling functions, either through cytoplasmic tails that contain immunoreceptor tyrosine-based inhibition motifs (ITIMs), or transmembrane regions that possess positively charged residues that allow an association with activating adaptor molecules containing immunoreceptor tyrosine-based activation motifs (ITAMs). ITIMs are characteristic of many innate (inhibitory) receptors [11] (Figure 1) and, upon tyrosine phosphorylation, recruit Src-homology 2 (SH2)-domain-containing tyrosine phosphatases, such as SHP-1 and SHP-2, and thereby regulate proximal cellular signaling pathways in a negative fashion. Transmembrane regions possessing positively charged residues are found in various mammalian IgSF members, including TCRs, and these can associate with ITAM-containing adaptor molecules such as CD3z, DAP12 and/or the Fc receptor (FcR)g chain [12]. Upon tyrosine phosphorylation, ITAMs recruit SH2-containing kinases, such as Syk and ZAP-70, which subsequently activate downstream signaling cascades. SIRPs: close, non-rearranging relatives of antigen receptors in mammals Members of the SIRP family of proteins have been described in mammals. There is also evidence for expression of SIRP genes in birds (T.K. van den Berg, unpublished). The first and best-characterized member of the SIRP family, SIRPa [other names include SH2-domain-containing phosphatase substrate-1 (SHPS-1), BIT (brain Ig-like

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Table 1. J-like sequences in IgSF membersa,b Molecule (species;gic)

J-like sequence (V domain)

Structure

ITIM

TM

Expression

Ligand

Igk (ra;204825) IgNAR (ns;699407) NARC (ws;15420366) TCRa (hu;1362966) SIRPa1 (hu;2052056) SIRPa2 (hu;18426911) SIRPaILA24 (bo;2842390) SIRPaCC149 (bo;2842388) SIRPa (mu;6671640) SIRPa (ra;13357220) SIRPb1 (hu;16174372) SIRPb2 (hu;17484397) SIRPb3 d1 (hu;17484393) SIRPb3 d2 (hu;17484393) SIRPb4 d4 (hu;18592524) SIRPb4 d5 (hu;18592524) SIRPg (hu;17484395) CD79b (hu;11038673) CD8b (hu;4826666) CD7 (hu;14776329) NKp30 (hu;17221621) DORA (hu;5031672) NITR10 (sp;6840838) NITR3.1 (zf;18369624) NITR1 (cc;17105071) NITR4 (cc;17105098) VCBP3 d1 (am;24528458) VCBP3 d2 (am;24528458)

QFNSRPYTFGAGTKLELN CTTDPWAACGDGTVLTVN YASYSWNEKGAGTVLTVK VLGYSTLTFGKGTMLLVS GSPDTEFKSGAGTELSVR SPDDVEFKSGAGTELSVR EHGDVEFKSGPGTHLTVN ERGDMEFKSGPGTHLTVS SEPDTEIQSGGGTEVYVL VEPDTEIKSGGGTTLYVL SPDDVEFKSGAGTELSVR SPENVEFKSGAGTELSVR LSEHSEMKSDEGTSVLVK RKPNRQYLSGQGTSLKVK GGPDMELKSGPGTELSVH IPANVEIKSGPGTQMSVR GRAIKEYQSGRGTQVFVT CNNTSEVYQGCGTELRVM IVGSPELTFGKGTQLSVV QAITEVNVYGSGTLVLVT EVLGLGVGTGNGTRLVVE VPEARAKQTGGGTTLVVR ILEFNSLEFGEGTLLQVR KDFLNRLMFGEGTILLRK EELNSSLYFSSGTVLVVE VTFLYEITFGQGTVLIVK FDSDEHNQFGMD-----------------TILKVQ

V-C1 V-C10 -(C)4d V-(C1)6 V-C1-TM V-C1-C1-TM V-C1-C1-TM V-C1-C1-TM V-C1-C1-TM V-C1-C1-TM V-C1-C1-TM V-C1-C1-TM V-C1-C1-TM V-V-TM V-V-TM C1-C1-C1-V-V-TM C1-C1-C1-V-V-TM V V-TM V-TM V-TM V-TM V-TM V-V/C2-TM V-V/C2-TM V-V/C2-TM V-V/C2-TM V-V V-V

nr nr nr 2 þ þ þ þ þ þ 2 2 2 2 2 2 nr 2 2 2 2 2 þ þ þ 2 nr nr

nr nr nr þ CD3 2 2 2 2 2 2 þ DAP12 2 þ þ þ þ nr 2 2 2 þ CD3 2 2 2 2 þ nr nr

B ? ? T my/neu my/neu my/neu my/neu my/neu my/neu my/neu ? ? ? ? ? ? B T/NK T/NK/HSC NK my/T ? ? ? ? int int

Ag ? ? pep þ MHC CD47 CD47 ? ? CD47 CD47 ? ? ? ? ? ? ? ? MHCI ? ? ? ? ? ? ? ? ?

Consensus

--------FGXGTXLXV

a

Relevant IgSF members that carry V-set domains with a C-terminal J-like sequence motif were identified by searches in TREMBL and PROSITE databases. The table lists several the characteristics of these molecules, including their J-like sequence (i.e. the C-terminal residues of the V-exon; consensus sequence motif is shown in red), overall structure (i.e. domain organization), the presence of cytoplasmic ITIMs, the presence of positively charged residues in TM regions (where relevant, associated ITAMcontaining adaptor molecules are indicated in superscript), cellular expression and ligand specificity. b Species abbreviations: am, amphioxus; bo, bovine; cc, channel catfish; hu, human; mu, murine; ns, nurse shark; ra, rat; sp, southern pufferfish; ws, wobblegong shark; zf, zebrafish. c Other abbreviations: Ag, antigen; B, B lymphocytes; DORA, downregulated by activation; gi, GenInfo identifier; HSC, hematopoietic stem cells; IgSF, immunoglobulin superfamily; int, intestinal cells; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif; MHC, major histocompatibility complex; my, myeloid cells; neu, neuronal cells; NK, natural killer cells; nr, not relevant; pep, peptide; T, T lymphocytes; TM, transmembrane. d The designation C10 in IgNAR indicates a truncated C1 domain; CD8 and VCBP also contain nonrelated domains but these are not indicated.

molecule with tyrosine-based activation motifs), macrophage fusion receptor (MFR), p84], is a cell-surface receptor composed of an extracellular region with a joined VJ segment, and two C1-like domains [13] (Figure 1). Each of the individual SIRPa Ig domains have , 30% amino acid identity to antigen receptor V and C1 domains [14]. The SIRPa cytoplasmic region contains four ITIMs, which can recruit SHP-1 and SHP-2 and thereby modulate signaling [13,15]. SIRPa has been described in humans [15], mice [16], rats [17] and cattle [18], and its expression is largely restricted to myeloid cells (i.e. macrophages, monocytes, granulocytes, dendritic cells, myeloid progenitors), hematopoietic stem cells and neurons [17,19]. On the basis of genomic evidence, the different SIRPa sequences that were described originally [15] appear to represent polymorphic variants, rather than products of different genes (T.K. van den Berg et al., unpublished). Polymorphisms occur predominantly in the V-set domain [20]. The broadly expressed CD47 molecule [also termed integrin-associated protein (IAP)] is an IgSF member with a single V-set ectodomain and has been identified as a cellular ligand for SIRPa, such that the SIRPa V-set Ig domain is responsible for CD47 binding [19,21,22]. Studies using CD47-deficient erythrocytes or macrophages from mice that lack the http://treimm.trends.com

SIRPa cytoplasmic domain have implicated SIRPa as a negative regulator of host cell phagocytosis by macrophages, suggesting that ligation of SIRPa by CD47 generates a signal that inhibits signaling by phagocytosis receptors [23,24,25]. Thus, by analogy to MHC class I molecules, which provide a signal that inhibits killing in natural killer (NK) cells through ITIM-containing NK receptors [11], CD47 might act as a marker of ‘self ’ that controls macrophage activities by ligation of SIRPa. Another interesting aspect of CD47 is that, as for MHC class I, homologs have been identified in viruses (e.g. pox viruses) and these could perhaps play a role in immune evasion by generating inhibitory signals through SIRPa [26]. Although the vaccinia CD47 homolog does not appear to be essential for virulence in a mouse model [27], studies with a natural pathogen (i.e. ectromelia virus in the mouse) should provide more clarity on this area. Two other closely related SIRP family members described in humans, SIRPb1 [28,29] and SIRPb2 [30], have an extracellular domain organization similar to SIRPa that includes J-like sequences in their V-set domains. However, both SIRPb1 and SIRPb2 have short cytoplasmic tails that lack ITIMs. Interestingly, SIRPb1 associates with DAP12, probably by a positively charged

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residue in the transmembrane region, and appears to function as an activating receptor [28]. The combination of these structural and signaling properties make SIRPb1 the closest non-rearranging relative of antigen receptors identified to date (Figure 1). In contrast to SIRPb1, SIRPb2 lacks a positively charged residue in the transmembrane region. In humans, SIRPs are encoded in a cluster on chromosome 20p13 [31] and the availability of the chromosome 20 draft sequence [32] has allowed the identification of three additional and more-divergent members of this family, designated SIRPb3, SIRPb4 and SIRPg, which also carry joined VJ segments (Table 1). SIRPb3 appears to encode a cell-surface receptor composed of two extracellular V-type Ig domains and a transmembrane region with a positively charged amino acid. SIRPb4 (which might constitute a pseudogene) has a peculiar extracellular region, with three N-terminal C1-type Ig domains and two membrane-proximal V-type Ig domains and, again, a transmembrane region with a positively charged amino acid. Finally, SIRPg encodes a putative secreted molecule with a single V domain (corresponding single V-domain-containing NITRs also have been described [33]; J. Yoder and G. Litman, unpublished). Database searches using the individual SIRP V domains show that, apart from other SIRP family members, antigen receptor chains and NITRs are among the closest relatives (25 – 30% amino acid identity). The presence of C1 domains clearly distinguishes SIRPa from other non-rearranging IgSF members (including NITR, see below) and further suggests a common origin with antigen receptors. The presence of more than one C1 domain in SIRP is also characteristic of the IgH chains found in all jawed vertebrates. The relatively low level of similarity between the two C1 domains (, 20%) suggests that this organization is not simply the result of exon duplication in a common SIRP ancestor, but could have been present in some more-primitive molecules, perhaps including a common antigen receptor/SIRP ancestor. What can the proposed evolutionary relationship between antigen receptors and SIRPs tell us about the possible function of antigen receptor predecessors? At first sight, it appears that the processes of regulation of phagocytosis (a function of SIRPa in macrophages) and cytotoxicity (a function of TCRs in T cells) have little in common. However, phagocytosis of apoptotic (or otherwise modified) host cells is an ancient capacity of multicellular organisms, essential for normal development and homeostasis. In this context, cell-mediated cytotoxicity could have evolved as a supporting mechanism to render (undesired) host cells apoptotic and ready for removal by phagocytes. In fact, it is clear that other IgSF members, such as FcRs on macrophages and NK cells, can provide signals that trigger both processes. Therefore, it seems most likely that the non-rearranging predecessors of antigen receptors were recognizing a self-ligand (possibly similar to MHC class I or CD47) and, through interaction with these, were regulating immune-cell-mediated cytotoxicity and/or phagocytosis of host cells. http://treimm.trends.com

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NITRs: a diversified family of IgSF members in fish related to antigen receptors NITR genes have been identified in four species of bony fish (pufferfish, zebrafish, channel catfish and trout) [10,33–35]. The typical NITR gene is composed of a V-set Ig ectodomain and a second Ig domain with a mixed V and C2 (V/C2) character, both of which can contain J-like sequences. Other NITRs consist only of a single V ectodomain. Many NITRs have cytoplasmic ITIMs that could act to recruit and signal through as-yet-uncharacterized fish SHPs. Other family members have transmembrane regions with positively charged residues and are therefore predicted to interact with adaptor molecules. In zebrafish, NITRs constitute a large and highly diversified family with over 30 individual genes and 140 different allelic variants characterized so far [34]; (J. Yoder and G. Litman, unpublished). A variety of different approaches, including the recent complete resolution of the nitr gene locus (J. Yoder and G. Litman, unpublished), have led us to conclude that the NITRs are encoded in a single chromosomal region that demonstrates considerable haplotypic variation (J. Yoder and G. Litman, unpublished). Although complex to interpret, the NITR chromosomal regions share a distant syntenic relationship with the region on human chromosome 19q13.3-q13.4 that includes the leukocyte receptor complex (LRC) [34]. The LRC (and its neighbouring area) encodes a variety of innate inhibitory or activating IgSF receptor families that regulate immune cell function, such as killer cell inhibitory receptors (KIRs); Ig-like transcript (ILT) and siglecs are encoded close to but outside the LRC [36] (for examples, see Figure 1). Members of these families regulate NK-cell cytotoxicity through interaction with MHC class I molecules (KIR, ILT) or other self-ligands such as sialic acids (siglecs), and this resembles the function of TCRs in cytotoxic T cells [11,37,38]. Crosslinking of an ITIM-containing NITR introduced into mammalian NK cells inhibits target-cell-induced activation of the mitogen-activated protein kinase pathway [34], which is known to play a crucial role in NK-cell killing. The highest levels of NITR expression are found in hematopoietic cells and tissues [33], but their precise cellular distribution and immunological function(s) remain to be established. It will be interesting to determine if, by analogy to antigen receptors and SIRPs, the NITRs interact with MHC class I or other ‘self ’ molecules. SIRPs, NITRs and the evolution of antigen receptors Because it remains beyond our limits to study the origins of antigen receptors directly, our understanding of this essential process must come from examining the probable descendents of the primordial receptors. The shared structural and functional properties of antigen receptors, SIRPs and NITRs create a remarkable dataset that previously have not been interpreted in an integrative manner. These multigene families constitute either an extraordinary example of convergence, or a true persistence of characteristics from the ‘primordial’ receptors that gave rise to these families. Favoring the latter possibility, we propose a relationship between the gene families upon

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NITR

VJ

VCBP

VC2J

VJ'

VJ'

VJ

VJ'

VJ

VJ

VJ*

C1 + transposon C1

SIRP

TCR or Ig TRENDS in Immunology

Figure 2. Proposed scheme for the evolution of antigen receptors and their relationship to SIRP, NITR and VCBP families. Note that the precursor is a transmembrane molecule and that the soluble VCBPs are probably derived. Abbreviations: C1, C1-set Ig domain; C2, C2-set Ig domain; VJ, V-set Ig domain containing J-like sequence; VJp, rearranging VJ-domain; VJ0 , VJ domain that contains a partial J-sequence; VC2J, mixed V/C2 Ig domain containing J-like sequence.

which a new model for the evolution of antigen receptors can be considered (Figure 2). First, the shared structural and functional properties between antigen receptors and SIRPs strongly suggest a common ancestor in early-jawed vertebrates and/or more-primitive vertebrates. This ancestor is proposed: (i) to be non-rearranging; (ii) to have a VJ-C1-TM structure; (iii) to interact with endogenous cellular self-ligands (possibly similar to CD47 or MHC); (iv) to possess the capacity to signal via ITIM or associated adaptor molecules; and (v) to regulate innate effector functions (e.g. cell-mediated cytotoxicity and/or phagocytosis). Importantly, descendents of this putative ancestral molecule would have constituted the target for the crucial transposition event that gave rise to rearranging antigen receptors and, as a result, adaptive immunity. Furthermore, a primordial IgSF cell-surface molecule with a joined VJ domain is predicted to have evolved into both the common antigen receptor/SIRP predecessor and the primordial NITR. The recent description in a protochordate of a diversified family of V-region-containing putative recognition molecules, termed VCBPs [39], provides possible insight into the origin of the VJ structure. VCBPs are composed of two V-set domains (as well as a chitin-binding domain) (Figure 1), each of which contains a partial J-related motif (Table 1). An interdomain recombination event could have given rise to a contiguous VJ structure. This roughly places the origin of this structure before the divergence of the jawed and jawless vertebrates. The identification of additional VJ-region-containing IgSF members in (early) http://treimm.trends.com

vertebrates and invertebrates, as well as a more detailed functional characterization of SIRPs, NITRs and other potentially informative gene families such as the VCBPs, is likely to help further evaluate the relationships proposed in Figure 2 and provide a better understanding about the origins of adaptive immunity. Acknowledgements We wish to thank Reina Mebius, Georg Kraal, Christine Dijkstra and Nico van Rooijen for their helpful suggestions. G.W.L. is supported by NIH grant AI23338.

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