- Email: [email protected]
Human natural killer cell activating receptors
Molecular Immunology 37 (2000) 1015– 1024 www.elsevier.com/locate/molimm
Review
Human natural killer cell activating receptors Roberto Biassoni a,*, Claudia Cantoni b,c, Michela Falco b,c, Daniela Pende a, Romano Millo b, Lorenzo Moretta b,c, Cristina Bottino a, Alessandro Moretta b a
Istituto Nazionale per la Ricerca sul Cancro, Laboratorio di Immunologia, IST/CBA, L.go R. Benzi, 10, 16132 Geno6a, Italy b Dipartimento di Medicina Sperimentale, Uni6ersita` degli Studi di Geno6a, Geno6a, Italy c Istituto Giannina Gaslini, Geno6a, Italy Received 13 March 2001; accepted 14 March 2001
Abstract Natural killer (NK) cells were poorly characterized until 10 years ago and few molecules expressed on their cell surface were known. Now the situation has changed dramatically, since a plethora of receptors characterized by opposite functions have been functionally and molecularly defined. NK cells express clonally distributed inhibitory receptors specific for different groups of HLA class I alleles, thus protecting normal cells from NK-mediated lysis. On the contrary, various activating receptors are involved in triggering of NK-mediated natural cytotoxicity. Their engagement induces human NK cells to kill target cells that are either HLA class I-negative or -deficient. Here a brief description of the activating receptors and coreceptor and of their ligand(s) is given. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Receptors; Natural killer; HLA
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1015
2. Activating HLA class I-specific receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1016
3. Natural cytotoxicity receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1017
4. NKG2D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1019
5. Activating coreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1019
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1021
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1021
1. Introduction Natural killer (NK) cells represent a first line of defense of the immune system against transformed and
* Corresponding author. Tel.: + 39-010-5737221; fax: +39-010354123. E-mail address: [email protected] (R. Biassoni).
virally infected cells (Trincheri, 1990; Biron, 1997). In humans, NK cells efficiently lyse abnormal cells that either lack the expression or express inadequate amounts of HLA class I molecules. In this context, it is known that downregulation of HLA class I expression is a frequent event during tumor transformation or following viral infection (Garrido, 1996; Garrido et al., 1997; Ploegh, 1998). The ability of human NK cells to
0161-5890/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 1 6 1 - 5 8 9 0 ( 0 1 ) 0 0 0 1 8 - 9
1016
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
discriminate between normal and HLA class I-deficient cells is due to the expression of clonally distributed HLA class I inhibitory receptors that, upon recruitment of specific phosphatases (SHP-1 and SHP-2) inhibit the NK-mediated cytotoxicity by acting on the triggering signal cascades (Olcese et al., 1996; Burshtyn et al., 1996; Campbell et al., 1996). A common structural feature of all inhibitory receptors is the presence in their intracytoplasmic tails of the Immune Tyrosine Inhibitory Motif (ITIM) sequences (Bolland and Ravetch, 1999). The inhibitory receptors belong to two distinct receptor families, the immunoglobulin superfamily (IgSF) and the C type lectin superfamily (Moretta et al., 1996, 1997; Lanier, 1998a; Long, 1999; Lopez-Botet et al., 1997). The different Killer Inhibitory Receptors (KIR) all belong to the Ig-SF and specifically recognize different groups of HLA class I alleles (Colonna and Samaridis, 1995; D’Andrea et al., 1995; Wagtmann et al., 1995; Pende et al., 1996; Dohring et al., 1996; Moretta et al., 1997). The genes coding for KIR have been mapped on chromosome 19q13.42 in a region called Leukocyte Receptor Complex (LRC) (Wende et al., 1998; Barten et al., 2001). The inhibitory receptor belonging to the C type lectin family is represented by a heterodimeric structure formed by CD94 and NKG2A molecules (Carretero et al., 1997; Lazetic et al., 1996; Brooks et al., 1997; Houchins et al., 1997) displays a specificity for the non classical HLA class I molecule HLA-E (Braud et al., 1998; Borrego et al., 1998; Lee et al., 1998). The CD94/NKG2A encoding genes have been mapped on chromosome 12p12-13 in a region called NK gene complex (Barten et al., 2001). Importantly, the HLA class I specific inhibitory receptors block NK-mediated cytotoxicity by down-regulating the function of different triggering receptors. Several molecules have been identified that are able to trigger NK-mediated cytotoxicity. These include CD16, CD2 and DNAM-1. CD16 (FcgRIII), the low affinity receptor for IgG, is able to transduce activating signals through its association with the g subunit of the high affinity IgE receptor (FcoRIg) and the CD3z subunit (Lanier et al., 1989; Orloff et al., 1990; Wirthmueller et al., 1992; Murakami and Ravetch, 1992). Following CD16 mAb-mediated crosslinking the Immunoreceptor Tyrosine-based Activating Motifs (ITAM) in the cytoplasmic tail of CD3z and FcoRIg molecules are tyrosine phosphorylated by the src family member p56lck and initiate the activating signal cascade. CD16 is involved in the Antibody Dependent Cell-mediated Cytotoxicity (ADCC), while its implication in NK-mediated natural cytotoxicity is still controversial (Mandelboin et al., 1999; Sivori et al., 2000a). CD16 is expressed on the majority of, but not all, human NK cells and on activated monocytes as well as on a T cell subset. CD2 is a 50 kDa surface protein belonging to the Ig-SF (Siliciano et al., 1985; Bolhuis et al., 1986) that is
expressed on a NK cell subset and on all T cells. CD2 engagement results in NK cell activation only in a fraction of CD2+ NK cells thus suggesting that it may function as a co-receptor during natural cytotoxicity. Similar to CD2, DNAM-1 is another broadly expressed surface molecule that has been implicated in cell adhesion (Shibuya et al., 1996). More recently, different NK receptors have been characterized that in most instances display an NK-restricted cell surface distribution and that appear to be directly involved in the initiation of NK-mediated natural cytotoxicity. These include HLA class I-specific and non-HLA class I-specific activating receptors (Biassoni et al., 2001; Moretta et al., 2001).
2. Activating HLA class I-specific receptors Upon ligand recognition these receptors trigger, rather than inhibit, the NK-mediated cytolysis (Moretta et al., 1995). Similar to HLA class I-specific inhibitory receptors, they belong to the Ig-SF or to C type lectin superfamily (Biassoni et al., 1996; Bottino et al., 1996; Cantoni et al., 1998; Houchins et al., 1997; Lanier et al., 1998b). Those belonging to the Ig-SF are represented by p50/KIR2DS molecules (Biassoni et al., 1996; Bottino et al., 1996), while CD94/NKG2C and CD94/NKG2E heterodimers belong to the C-type lectin superfamily (Houchins et al., 1991; Chang et al., 1995) (Fig. 1). These receptors display a high degree of amino acid sequence identity with the corresponding inhibitory ones in their extracellular portions, thus indicating that they may recognize the same groups of HLA class I alleles as their inhibitory counterparts. Indeed, this has been demonstrated both at the functional and at the molecular level for p50.1/KIR2DS1, p50.2/KIR2DS2 and CD94/NKG2C (Biassoni et al., 1996, 1997; Braud et al., 1998; Borrego et al., 1998; Lee et al., 1998). The functional role of these activating receptors is still debated. It has been suggested that they may recognize ‘unusual’ or ‘non-self’ peptides in the context of HLA class I molecules. On the other hand, it is also possible that they may be involved in killing of HLA class I positive target cells that have undergone cell surface downregulation of protective alleles (Moretta et al., 2001). HLA class I-specific activating receptors display some common structural features (Biassoni et al., 1996). Thus, different from their inhibitory counterparts, the cytoplasmic tail of activating receptors does not contain ITIM sequences, whereas a charged residue (lysine) characterizes the transmembrane portion. This residue is involved in the association of activating receptors with the ITAM-containing KARAP/DAP12 molecules that are involved in the transduction of activating signals (Olcese et al., 1997; Lanier et al., 1998c; Bottino et al., 2000a; Campbell et al., 1998; Lanier et
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
al., 1998b). It is of note that the gene coding for KARAP/DAP12 has been mapped on chromosome 19q centromeric to KIR genes (Barten et al., 2001). Although these triggering receptors are able to initiate NK cell activation and target cell lysis, they clearly cannot be responsible for natural cytotoxicity against HLA class I-negative target cells. This indicates the existence of additional triggering NK receptors able to recognize non-HLA class I ligands on target cells. Some of these receptors have been recently identified and collectively termed Natural Cytotoxicity Receptors (NCR) (Moretta et al., 2000a,b, 2001; Bottino et al., 2000b; Biassoni et al., 2001)
3. Natural cytotoxicity receptors The common characteristics of NCR are their selective expression on NK cells and their ability to induce NK cell triggering in a HLA class I-independent fashion. Moreover, mAb-mediated interference of NCR/ligand recognition results in the inhibition of natural cytotoxicity. Another important feature is that under physiological conditions (i.e. against autologous HLA class I+ target cells), the NK cell activation induced via NCR is negatively regulated by HLA class I-specific receptors. It is of note that NCR identified so far are able to play either a cooperative or a synergistic role in the activation of NK-mediated cytolysis against different types of tumor target cells. This demonstrates that
1017
natural cytotoxicity is the result of multiple receptor/ ligand interactions between NK and target cells (Moretta et al., 2000a,b, 2001). So far three different NCR, NKp46, NKp30 and NKp44, have been characterized, both at the functional and at the molecular level (Fig. 2). NKp46, the first NCR identified, is selectively expressed by all resting and activated NK cells (Sivori et al., 1997). It represents the main receptor responsible for natural cytotoxicity and its mAb-mediated crosslinking also induces Ca++ mobilization and cytokine release. NKp46 is involved in lysis of different target cells, including both normal and tumor cells of autologous, allogeneic or xenogeneic origin (Sivori et al., 1999). In particular, it was found to be implicated in the NK-mediated lysis of the majority of human tumors belonging to different histotypes, including lung, liver, breast carcinoma, melanoma and EBV-infected cell lines. The surface density of NKp46 may differ in different NK cells or in different individuals. Importantly, the magnitude of NK-mediated cytolytic activity correlate with the level of NKp46 surface expression, indicating that NKp46 plays a key role in natural cytotoxicity (Sivori et al., 1999). A recent report shows that NKp46 is able to recognize in a sialic acid-dependent manner viral ligands, such as haemagglutinin of influenza virus or haemagglutinin–neuraminidase of parainfluenza virus (Mandelboim et al., 2001). It is of note, however, that most target cells that are killed via NKp46 do not express these ligands. This indicates that NKp46 recog-
Fig. 1. HLA class I-specific activating receptors. Receptors specific for two distinct group of HLA-C class I alleles belongs to the Ig-SF. Their transmembrane portion, display the positively charged amino acid lisine that is involved in the association with KARAP/DAP12 ITAM-bearing signal-transducing molecules. In particular, p50.1/KIR2DS1 receptor recognizes HLA-Cw4 and other HLA-C alleles sharing Asn (N) 77 and Lys (K) 80, while p50.2/KIR2DS2 is specific for HLA-Cw3 and related HLA-C alleles sharing Ser (S) 77 and Asn (N) 80 in the a1 domain of the heavy chain, as shown. CD94/NKG2-C and -E belongs to the C type lectin family of receptors and display HLA-E specificity.
1018
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
Fig. 2. Molecular structure of NCR (NKp46, NKp44, NKp30) and NKG2D and their association with distinct signal transducing molecules. NCR belong to the Immunoglobulin superfamily, while NKG2D is a member of the C type lectin receptor family. NKp46 displays an extracellular portion characterized by two Ig-like domains of the C2 type. An extracellular region containing a single Ig-like domain of the V type characterizes NKp30 and NKp44. NCR transmembrane portions contain positively charged amino acids that are supposed to be crucial for their association with distinct signal transducing molecules bearing typical ITAM. NKG2D associate with KAP10/DAP10 polypeptide that upon tyrosine phosphorylation recruits phosphatidylinositol 3-kinase. Putative N-linked or O-linked glycosilation sites are indicated as horizontal or angled lines, respectively.
nize on target cells additional still undefined ligands that are likely to play a major role in NK-cell activation via this receptor. NKp46 is a glycoprotein belonging to the Ig-SF characterized by two extracellular Ig-like domains of the C2 type (Pessino et al., 1998). The transmembrane region contains an arginine residue possibly involved in the association of NKp46 with the ITAM-bearing molecules CD3z and FcoRIg. These associated polypeptides are involved in the signal transduction initiated by NKp46 receptor. The gene coding for NKp46 has been mapped on chromosome 19 (Pessino et al., 1998) in the LRC region, just telomeric to the FcaR (CD89), whereas the KIR multigene family is located centromeric to the FcaR gene (Barten et al., 2001). The NKp46 locus is also conserved in rodents (both mouse and rat) (Biassoni et al., 1999; Falco et al., 1999) and in non human primates such as Macaca fascicularis (De Maria et al., 2001). In accordance with the ability of human NKp46 to recognize murine target cells, a murine homologue of NKp46 has been isolated and cloned, suggesting a possible conservation of NKp46 function during evolution. Moreover, the macaque NKp46 was found to share both function and cellular distribution with its human counterpart (De Maria et al., 2001). NKp30 shares some common features with NKp46. In particular, NKp30 is selectively expressed by all NK cells either resting or activated, and mAb-mediated crosslinking induces Ca++ flux, cytotoxicity and cytokine production (Pende et al., 1999). NKp30 is a 30 kDa glycoprotein belonging to the Ig-SF, that displays a single extracellular IgV domain and a transmembrane portion characterized by an arginine residue (Pende et al., 1999). NKp30 transduces activating signals via the
association with the CD3z chain. Molecular cloning revealed the identity of NKp30 cDNA with the 1C7 gene (Nalabolu et al., 1996; Neville and Campbell, 1999; Sivakamasundari et al., 2000). The latter was mapped on chromosome 6p at the telomeric end of the HLA class III region between the LTB (lymphotoxin beta or TNF superfamily member 3) and AIF1 (allograft inflammatory factor 1) genes (Neville and Campbell, 1999). In M. fascicularis, a gene has been identified that encodes a functional NKp30 receptor (De Maria et al., 2001), while in the mouse only a NKp30 pseudogene has been identified so far (Sivakamasundari et al., 2000). Altogether these data suggest that NKp30 gene may have appeared more recently than NKp46 in evolution. Different from NKp46 and NKp30 receptors, NKp44 is selectively expressed by interleukin-2 (IL-2) cultured NK cells, thus representing the first marker for the identification of activated NK cells (Vitale et al., 1998). This suggests that NKp44 may be, at least in part, responsible for the enhanced cytolytic activity of activated NK cells as compared with freshly isolated NK lymphocytes (Grimm, 1982; Ferrini et al., 1987). NKp44 is another member of the Ig-SF characterized, as NKp30, by a single extracellular Ig V domain (Cantoni et al., 1999). The transmembrane portion contains the charged lysine residue possibly involved in NKp44 association with KARAP/DAP12 polypeptides. These ITAM-containing molecules are necessary both for the surface expression of NKp44 and for transducing activating signals. The NKp44 gene maps on chromosome 6, 120 and 180 kb from the TREM-1 (triggering receptor expressed on myeloid cells-1) and TREM-2 genes. TREM genes encode two novel KARAP/DAP12-associated receptors expressed either on neutrophils and
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
monocytes (TREM-1) or on macrophages and dendritic cells (TREM-2) (Bouchon et al., 2000). At variance with the other NCR, NKp44 gene has not been identified so far in species different from humans. There is a coordinated surface expression of the three NCR, thus it is possible to identify NK clones with NCRbright or NCRdull phenotype (Pende et al., 1999; Sivori et al., 1999, 2000a). The cellular ligands of NCR have not yet been characterized. The functional data indicate that such ligands appear to be expressed on both normal and tumor cells. However, it is possible that their expression may vary following cellular stress, cellular activation or tumor transformation. It is of note that some tumor cells seem to lack certain NCR ligands. This suggests the existence of an in vivo mechanism of tumor escape from NK-mediated recognition based on the downregulation of NCR-specific ligand molecules. Since NCR play a major role in the induction of natural cytotoxicity, the characterization of their ligands will be important for tumor cell typing as well as for novel immunotherapy approaches.
4. NKG2D NKG2D is a member of the C-type lectin superfamily (Wu et al., 1999; Bauer et al., 1999) that is only distantly related to the other members of the NKG2 family (Houchins et al., 1991) and does not associate with CD94, being expressed as a homodimer (Wu et al., 1999). Its function and expression depend upon the association with a newly identified signaling subunit, termed DAP10 (Wu et al., 1999) or KAP10 (Chang et al., 1999) (Fig. 2). DAP10/KAP10 upon tyrosine phosphorylation recruits phosphatidylinositol 3-kinase (Wu et al., 1999; Chang et al., 1999; Wu et al., 2000). Gene coding for this transducing polypeptide has been mapped on chromosome 19q just telomeric to KARAP/ DAP12 gene (Barten et al., 2001). Different from NCR, NKG2D expression is not confined to NK cells, since it is also expressed by virtually all TCR g/d+ and CD8+ TCR a/b+ cells. In NK cell clones, NKG2D was found to complement the role of NCR in tumor cell lysis (Pende et al., 2001). Thus, available data suggest that NK cell triggering in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. The first identified ligands recognized by NKG2D were the stress-inducible molecules MICA and MICB (Groh et al., 1996, 1999; Bauer et al., 1999) that are encoded within the human MHC complex. These molecules have been first described on epithelial tumors (Groh et al., 1999), but also other tumor cell lines (i.e. melanomas) were found to be MICA+ (Pende et al., 2001). Recently, ULBP (UL16 binding proteins) have been described as additional NKG2D ligands, ex-
1019
pressed in a variety of cells and tissues (Cosman et al., 2001). On the other hand, still undefined additional ligands may exist, since MICA−/B− ULBP− cells (i.e. Daudi cell line and PHA blasts) appeared to be lysed in a NKG2D-dependent manner. NK cell triggering via NKG2D has been shown to override the negative signaling generated by the engagement of HLA class I-specific inhibitory receptors (Bauer et al., 1999). On the contrary, a recent report showed that, similar to NCR, the NKG2D-mediated cytolytic activity is under the control of HLA class I inhibitory receptors. Indeed, NKG2D-mediated activation of NK cells could be strongly inhibited by the simultaneous engagement of NKG2D and KIR by specific mAbs or by MICA and HLA class I molecules expressed on target cells (Pende et al., 2001).
5. Activating coreceptors Other surface molecules participate in the induction of NK cell triggering against certain target cell types. One of these molecules is represented by 2B4 (CD244) (Fig. 3). 2B4 is expressed by virtually all NK cells (resting and IL2 cultured) and by monocytes, basophils and a CD8+ T cells subset (Nakajima et al., 1999). The natural ligand of 2B4 is CD48 molecule expressed on the cell surface of T, B (fresh and EBV transformed), NK cells, monocytes and endothelial cells (Latchman et al., 1998; Brown et al., 1998; Kubin et al., 1999). 2B4 induces NK cell activation as demonstrated by the use of anti-2B4 mAb in redirected killing assay against FcgR+ murine targets (Moretta et al., 1992; Valiante and Trinchieri, 1993). However, analysis at clonal level revealed that this effect was confined to NK cells expressing high NCR surface densities. This suggested that the engagement of NKp46 (by ligand expressed on murine targets) may provide the first signal necessary for the subsequent responsiveness to 2B4 engagement by specific mAb or by the specific ligand (CD48) expressed on target cells. This supported the notion that 2B4 acts as a coreceptor during natural cytotoxicity against CD48+ targets (Sivori et al., 2000b). Structurally, 2B4 is a type I transmembrane protein (Latchman et al., 1998; Tangye et al., 1999; Boles et al., 1999; Kubin et al., 1999) belonging to the CD2 subfamily, which includes CD48, CD58, CD84, CD150 (also termed SLAM) and Ly9. All the CD2 subfamily genes have been located in two clusters on chromosome 1, in particular CD2 and CD58 are located at 1p13.1 whereas Ly9, CD48 and 2B4 at 1q21-23 (Tangye et al., 2000a). These genes are likely to have arisen in a series of gene duplication events, and duplication of the entire chromosomal region is likely to have given two pericentric regions. The extracellular portions of the CD2 subfamily members display similar structure being com-
1020
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
posed of a N terminal non-disulfide bonded V domain and a membrane-proximal C2 domain, the only exception being represented by Ly9 that shows two V-C2 modules. On the other hand, the cytoplasmic tails of the various members of this family are heterogeneous. CD48 is a GPI-linked surface molecule, whereas alter-
Fig. 3. Molecular structure of activating coreceptors. 2B4 is a type I transmembrane protein belonging to the CD2 subfamily, which includes CD48, CD58, CD84, CD150 and Ly9. 2B4 cytoplasmic region contains four tyrosine-based motifs characterized by the TxYxxV/I consensus sequence, implicated in the association with a small cytoplasmic polypeptide termed Src homology 2 domain-containing protein (SH2D1A) (or SLAM-associated protein SAP) and with SHP phosphatases. NKp80 is a type II transmembrane protein belonging to the C type lectin superfamily.
natively spliced forms of CD58 give rise to either a transmembrane form with a short (12 amino acid) cytoplasmic tail or a GPI-anchored protein. CD2, CD84, CD150, 2B4 and Ly9 are characterized by tails of different length (70–180 amino acids). Importantly, CD150, CD84, Ly9 and 2B4 cytoplasmic regions contain two or more tyrosine-based motifs characterized by the TxYxxV/I consensus sequence. Recently, this motif has been implicated in the association with a small cytoplasmic polypeptide termed Src homology 2 domain-containing protein (SH2D1A) (or SLAM-associated protein SAP) (Poy et al., 1999). The signal transducing pathway initiated via 2B4 has been recently clarified. 2B4 lacks both ITAM sequence in the cytoplasmic tail and charged amino acids in the transmembrane portion. In agreement with the latter finding, no association with ITAM-bearing polypeptides could be detected. On the other hand, it has been demonstrated that in human NK cells 2B4 associates with SHP-1 and that cell treatment with sodium pervanadate leads phosphorylation of 2B4 and its consequent association with SH2D1A. These results suggested that SH2D1A may sustain the 2B4-mediated triggering response by preventing the generation of inhibitory signals mediated by SHP-1 (Parolini et al., 2000). Along this line, it has been demonstrated that in NK cells derived from patients affected by X-linked lymphoproliferative (XLP) disease 2B4 displays a dramatically altered function. XLP patients are characterized by critical mutations in the SH2D1A encoding gene (Sayos et al., 1998; Coffey et al., 1998; Nichols et al., 1998). Due to the absence of a functional SH2D1A protein 2B4 engagement by the specific ligand (CD48), expressed at high densities on EBV infected cells, results in inhibitory rather than activating signals (Parolini et al., 2000; Benoit et al., 2000; Nakajima et al., 2000; Tangye et al., 2000b). This may provide a possible explanation of the inefficient control of EBV infection in XLP patients. A recent study demonstrated that 2B4 is constitutively associated with the linker for the activation of T cells (LAT). Indeed, antibody-mediated engagement of 2B4 resulted in tyrosine phosphorylation of 2B4 and of the associated LAT molecules. Tyrosine phosphorylation of LAT leads in turn to the recruitment of cytoplasmic signaling molecules, such as PLCg and Grb2 (Bottino et al., 2000c). A novel triggering molecule has been recently characterized at the functional, biochemical and molecular level. This molecule, termed NKp80 (Vitale et al., 2001), is expressed by all NK cells (fresh and activated) and by a small CD56+ T cell subset (Fig. 3). Functional studies revealed that NK cells display a marked heterogeneity in the magnitude of cytolytic responses to anti NKp80 mAb and that, as earlier demonstrated for 2B4, this correlates with the NKp46 surface density. This data lead to the conclusion that also NKp80 may
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
function as a coreceptor in NK cell mediated cytotoxicity. Molecular cloning revealed that NKp80 is a type II transmembrane protein belonging to the C type lectin superfamily. Although the activating signaling pathway initiated via NKp80 is still undefined, the lack of charged amino acid in the transmembrane region suggests that NKp80 does not transduce signals via the association with ITAM bearing polypeptides such as CD3z, FcoRIg, DAP10 and DAP12. It is possible, however, that the two tyrosine-based motifs (not belonging to typical ITAM sequences) present in the NKp80 cytoplasmic tail, may play a role in the NKp80mediated signaling. Comparison of the cDNA coding for NKp80 in GenBank database revealed its identity with the recently identified KLRF1 cDNA (RodaNavarro et al., 2000). The KLRF1 gene has been mapped in the NKC on chromosome 12p12-p13 telomeric to CD94 and centromeric to AICL. NKp80 ligand(s) is still unknown. Functional studies demonstrated that this receptor cooperates with NCR in the lysis of PHA blasts while does not appear to be involved in the NK-mediated killing of various tumor cells including T cell leukemias. Taken together, these data suggest that NKp80-specific ligand(s) may be either restricted to certain cell types or lost during tumor transformation.
Acknowledgements This work was supported by grants awarded by Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.), Istituto Superiore di Sanita` (I.S.S.), Ministero della Sanita`, and Ministero dell’Universita` e della Ricerca Scientifica e Tecnologica (M.U.R.S.T.) and Consiglio Nazionale delle Ricerche, Progetto Finalizzato Biotecnologie. The financial support of TelethonItaly (grant no.E.0892) is gratefully acknowledged.
References Bauer, S., Groh, V., Wu, J., Steinle, A., Phillips, J.H., Lanier, L.L., Spies, T., 1999. Activation of NK cells and T cells by NKG2D a receptor for stress-inducible MICA. Science 285, 727 – 729. Barten, R., Torkar, M., Haude, A., Trowsdale, J., Wilson, M.J., 2001. Divergent and convergent evolution of NK-cell receptors. Trends Immunol. 22, 52 –57. Benoit, L., Wang, X., Pabst, H.F., Dutz, J., Tan, R., 2000. Defective NK cell activation in X-linked lymphoproliferative disease. J. Immunol. 165, 3549 –3553. Biassoni, R., Cantoni, C., Falco, M., Verdiani, S., Bottino, C., Vitale, M., Conte, R., Poggi, A., Moretta, A., Moretta, L., 1996. The HLA.C specific ‘activatory’ and ‘inhibitory’ natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions. J. Exp. Med. 183, 645 –650.
1021
Biassoni, R., Pessino, A., Malaspina, A., Cantoni, C., Bottino, C., Sivori, S., Moretta, L., Moretta, A., 1997. Role of amino acid position 70 in the binding affinity of p50.1 and p58.1 receptors for Cw4 molecules. Eur. J. Immunol. 27, 3095 – 3099. Biassoni, R., Pessino, A., Bottino, C., Pende, D., Moretta, L., Moretta, A., 1999. The murine homologue of the human NKp46 a triggering receptor involved in the induction of natural cytotoxicity. Eur. J. Immunol. 29, 1014 – 1020. Biassoni, R., Cantoni, C., Pende, D., Sivori, S., Parolini, S., Vitale, M., Bottino C., Moretta, A., 2001. Human natural killer cell receptors and coreceptors. Immunol. Rev., in press. Biron, C.A., 1997. Activation and function of natural killer cell responses during viral infections. Curr. Opin. Immunol. 9, 24 –34. Boles, K.S., Nakajima, H., Colonna, M., Chuang, S.S., Stepp, S.E., Bennett, M., Kumar, V., Mathew, P.A., 1999. Molecular cloning of a novel natural killer cell receptor homologous to mouse 2B4. Tissue Antigens 54, 27 – 34. Bolhuis, R.L., Roozemond, R.C., Van de Griend, R.J., 1986. Induction and blocking of cytolysis in CD2 +, CD3− NK and CD2+ , CD3+ cytotoxic T lymphocytes via CD2 50 kDa sheep erythrocyte receptor. J. Immunol. 136, 3939 – 3944. Bolland, S., Ravetch, J.V., 1999. Inhibitory pathways triggered by ITIM-containing receptors. Adv. Immunol. 72, 149 – 177. Borrego, F., Ulbrecht, M., Weiss, E.H., Coligan, J.E., Brooks, A.G., 1998. Recognition of Human Histocompatibility Leukocyte Antigen (HLA)-E complexed with HLA class I signal sequencederived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J. Exp. Med. 187, 813 – 818. Bottino, C., Sivori, S., Vitale, M., Cantoni, C., Falco, M., Pende, D., Morelli, L., Augugliaro, R., Semenzato, G., Biassoni, R., Moretta, L., Moretta, A., 1996. A novel surface molecule homologous to the p58/p50 family of receptors is selectively expressed on a subset of human natural killer cells and induces both triggering of cell functions and proliferation. Eur. J. Immunol. 26, 1816 – 1824. Bottino, C., Falco, M., Sivori, S., Moretta, L., Moretta, A., Biassoni, R., 2000a. Identification of natural p50.2/KIR2DS mutants unable to transduce activating signals. Eur. J. Immunol. 30, 3569 – 3574. Bottino, C., Biassoni, R., Millo, R., Moretta, L., Moretta, A., 2000b. The human natural cytotoxicity receptors (NCR) that induce HLA class I-independent NK cell triggering. Human Immunol. 61, 1 – 6. Bottino, C., Augugliaro, R., Castriconi, R., Nanni, M., Biassoni, R., Moretta, L., Moretta, A., 2000c. Analysis of the molecular mechanism involved in 2B4-mediated NK cell activation: evidence that human 2B4 is physically and functionally associated with the linker for activation of T cells. Eur. J. Immunol. 30, 3718 –3722. Bouchon, A., Dietrich, J., Colonna, M., 2000. Inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J. Immunol. 164, 4991 – 4995. Braud, V.M., Allan, D.S.J., O’Callaghan, C.A., Soderstrom, K., D’Andrea, A., Ogg, G.S., Lazetic, S., Young, N.T., Bell, J.I., Phillips, J.H., Lanier, L.L., McMichael, A.J., 1998. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795 – 799. Brooks, A.G., Posch, P.E., Scorzelli, C.I., Borrego, F., Coligan, J.E., 1997. NKG2A complexed with CD94 defines a novel inhibitory NK cell receptor. J. Exp. Med. 185, 795 – 800. Brown, M.H., Boles, K., van der Merwe, P.A., Kumar, V., Mathew, P.A., Barclay, A.N., 1998. 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. J. Exp. Med. 188, 2083 – 2090. Burshtyn, D.N., Scharenberg, A.M., Wagtmann, N., Rajagopalan, S., Berrada, K., Yi, T., Kinet, J.P., Long, E.O., 1996. Recruitment of tyrosine phosphatase HCP by the killer cell inhibitory receptor. Immunity 4, 77 – 85.
1022
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
Campbell, K.S., Dessing, M., Lopez-Botet, M., Cella, M., Colonna, M., 1996. Tyrosine phosphorilation of a human killer inhibitory receptor recruits protein phosphatase 1C. J. Exp. Med. 184, 93– 100. Campbell, K.S., Cella, M., Carretero, M., Lopez-Botet, M., Colonna, M., 1998. Signaling through human killer cell activating receptors triggers tyrosine phosphorylation of an associated protein complex. Eur. J. Immunol. 28, 599 –609. Cantoni, C., Biassoni, R., Pende, D., Sivori, S., Accame, L., Pareti, L., Semenzato, G., Moretta, L., Moretta, A., Bottino, C., 1998. The activating form of CD94 receptor complex. CD94 covalently associates with the Kp39 protein that represents the product of the NKG2-C gene. Eur. J. Immunol. 28, 327 – 338. Cantoni, C., Bottino, C., Vitale, M., Pessino, A., Augugliaro, R., Malaspina, A., Parolini, S., Moretta, L., Moretta, A., Biassoni, R., 1999. NKp44, a triggering receptor involved in tumor cell lysis by activated human natural killer cells, is a novel member of the immunoglobulin superfamily. J. Exp. Med. 189, 787 –796. Carretero, M., Cantoni, C., Bello´ n, T., Bottino, C., Biassoni, R., Rodrı´guez, A., Pe´ rez-Villar, J.J., Moretta, L., Moretta, A., Lo´ pezBotet, M., 1997. The CD94 and NKG2-A C-type lectins covalently assamble to form a NK cell inhibitory receptor for HLA class I molecules. Eur. J. Immunol. 27, 563 – 567. Chang, C., Rodriguez, A., Carretero, M., Lopez-Botet, M., Phillips, J.H., Lanier, L.L., 1995. Molecular characterization of human CD94: a type II membrane glycoprotein related to the C-type lectin superfamily. Eur. J. Immunol. 25, 2433 – 2437. Chang, C., Dietrich, J., Harpur, A.G., Lindquist, J.A., Haude, A., Loke, Y.W., King, A., Colonna, M., Trowsdale, J., Wilson, M.J., 1999. KAP10, a novel transmembrane adapter protein genetically linked to DAP12 but with unique signaling properties. J. Immunol. 163, 4651 – 4654. Coffey, A.J., Brooksbank, R.A., Brandau, O., Oohashi, T., Howell, G.R., Bye, J.M., Cahn, A.P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., Leversha, M., Huckle, E., Shaw-Smith, C.J., Dunham, A., Rhodes, S., Schuster, V., Porta, G., Yin, L., Serafini, P., Sylla, B., Zollo, M., Franco, B., Bolino, A., Seri, M., Lanyi, A., Davis, J.R., Webster, D., Harris, A., Lenoir, G., de St Basile, G., Jones, A., Behloradsky, B.H., Achatz, H., Murken, J., Fassler, R., Sumegi, J., Romeo, G., Vaudin, M., Ross, M.T., Meindl, A., Bentley, D.R., 1998. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat. Genet. 20, 129 – 135. Colonna, M., Samaridis, J., 1995. Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by Human natural killer cells. Science 268, 405 –408. Cosman, D., Mullberg, J., Sutherland, C.L., Chin, W., Armitage, R., Fanslow, W., Kubin, M., Chalupny, N.J., 2001. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14, 123 – 133. D’Andrea, A., Chang, C., Franz-Bacon, K., McClanahan, T., Phillips, J.H., Lanier, L.L., 1995. Molecular cloning of NKB1. A natural killer cell receptor for HLA-B allotypes. J. Immunol. 155, 2306 – 2310. De Maria, A., Biassoni, R., Fogli, M., Rizzi, M., Cantoni, C., Conte, R., Costa, P., Mavilio, D., Cafaro, A., Moretta, A., Moretta, L., 2001. Identification, molecular cloning and functional characterization of NKp46 and NKp30 Natural Cytotoxicity Receptors in Macaca fascicularis (Macaca Rhesus) NK cells. (submitted) Dohring, C., Scheidegger, D., Samaridis, J., Cella, M., Colonna, M., 1996. A human killer inhibitory receptor specific for HLA-A. J. Immunol. 156, 3098 –3101. Falco, M., Cantoni, C., Bottino, C., Moretta, A., Biassoni, R., 1999. Identification of the rat homologue of the human NKp46 triggering receptor. Immunol. Lett. 68, 411 –414.
Ferrini, S., Miescher, S., Zocchi, M.R., Von Fliedner, V., Moretta, A., 1987. Phenotypic and functional characterization of recombinant interleukin-2 (rIL-2)-induced killer cells: analysis at the population and the clonal level. J. Immunol. 138, 1297 –1302. Garrido, F., 1996. MHC molecules in normal and neoplastic cells. Int. J. Cancer 6, 1 – 10. Garrido, F., Ruiz-Cabello, F., Cabrera, T., Pe´ rez-Villar, J.J., Lo`pezBotet, M., Duggan-Keen, M., Stern, P.L., 1997. Implications for immunosurveillance of altered HLA-class I phenotypes in human tumours. Immunol. Today 18, 89 – 95. Grimm, E., 1982. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin-2-activated autologous human peripheral blood lymphocytes. J. Exp. Med. 155, 1823 – 1841. Groh, V., Bahram, S., Bauer, S., Herman, A., Beauchamp, M., Spies, T., 1996. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc. Natl. Acad. Sci. USA 93, 12445 – 12450. Groh, V., Rhinehart, R., Secrist, H., Bauer, S., Grabstein, K.H., Spies, T., 1999. Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc. Natl. Acad. Sci. USA 96, 6879 – 6884. Houchins, J.P., Yabe, T., McSherry, C., Bach, F.H., 1991. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. J. Exp. Med. 173, 1017 – 1020. Houchins, J.P., Lanier, L.L., Niemi, E., Phillips, J.H., Ryan, J.C., 1997. Natural killer cell cytolytic activity is inhibited by NKG2-A and activated by NKG2-C. J. Immunol. 158, 3603 – 3609. Kubin, M.Z., Parsley, D.L., Din, W., Waugh, J.Y., Davis-Smith, T., Smith, C.A., Macduff, B.M., Armitage, R.J., Chin, W., Cassiano, L., Borges, L., Petersen, M., Trinchieri, G., Goodwing, R.G., 1999. Molecular cloning and biological characterization of NK cell activation-inducing ligand, a counterstructure for CD48. Eur. J. Immunol. 29, 3466 – 3477. Lanier, L.L., 1998a. NK cell receptors. Annu. Rev. Immunol. 16, 359 – 393. Lanier, L.L., Corliss, B., Wu, J., Phillips, J.H., 1998b. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity 8, 693 – 701. Lanier, L.L., Corliss, B.C., Jun, W., Leong, C., Phillips, J.H., 1998c. Immunoreceptor DAP12 bearing a tyrosine-based activation motifs is involved in activating NK cells. Nature 391, 703 –707. Lanier, L.L., Yu, G., Phillips, J.H., 1989. Co-association of CD3 zeta with a receptor (CD16) for IgG Fc on human natural killer cells. Nature 342, 803 – 805. Latchman, Y., McKay, P.F., Reiser, H., 1998. Identification of the 2B4 molecule as a counter-receptor for CD48. J. Immunol. 161, 5809 – 5812. Lazetic, S., Chang, C., Houchins, J.P., Lanier, L.L., Phillips, J.H., 1996. Human Natural killer cell receptors involved in MHC class I recognition are disulphide-linked heterodimers of CD94 and NKG2 subunits. J. Immunol. 157, 4741 – 4745. Lee, N., Llano, M., Carretero, M., Ishitani, A., Navarro, F., Lo`pezBotet, M., Gherarty, D., 1998. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc. Natl. Acad. Sci. USA 95, 5199 – 5204. Long, E.O., 1999. Regulation of immune responses through inhibitory receptors. Annu. Rev. Immunol. 17, 875 – 904. Lopez-Botet, M., Pe´ rez-Villar, M., Carretero, A., Rodrı`guez, I., Melero, I., Bellon, T., Llano, M., Navarro, F., 1997. Structure and function of the CD94 C-type lectin receptor complex involved in the recognition of HLA class I molecules. Immunol. Rev. 155, 165 – 174. Mandelboin, O., Malik, P., Davis, D.M., Jo, C.H., Boyson, J.E., Strominger, J.L., 1999. Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity. Proc. Natl. Acad. Sci. USA 96, 5640 – 5644.
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024 Mandelboim, O., Lieberman, N., Lev, M., Paul, L., Arnon, T.I., Bushkin, Y., Davis, D.M., Strominger, J.L., Yewdell, J.W., Porgador, A., 2001. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409, 1055 – 1060. Moretta, A., Bottino, C., Tripodi, G., Vitale, M., Pende, D., Morelli, L., Augugliaro, R., Barbaresi, M., Ciccone, E., Millo, R., Moretta, L., 1992. Novel surface molecules involved in human NK cell activation and triggering of the lytic machinery. Int. J. Cancer Suppl. 7, 6 – 10. Moretta, A., Sivori, S., Vitale, M., Pende, D., Morelli, L., Augugliaro, R., Bottino, C., Moretta, L., 1995. Existence of both inhibitory (p58) and activatory (p50) receptors for HLA.C molecules in human natural killer cells. J. Exp. Med. 182, 875 – 884. Moretta, A., Bottino, C., Vitale, M., Pende, D., Biassoni, R., Mingari, M.C., Moretta, L., 1996. Receptors for HLA-class I molecules in human natural killer cells. Annu. Rev. Immunol. 14, 619 – 648. Moretta, A., Biassoni, R., Bottino, C., Pende, D., Vitale, M., Poggi, A., Mingari, M.C., Moretta, L., 1997. Major histocompatibility complex class I-specifc receptors on human natural killer and T lymphocytes. Immunol. Rev. 155, 105 –117. Moretta, A., Biassoni, R., Bottino, C., Mingari, M.C., Moretta, L., 2000a. Natural cytotoxicity receptors that trigger human NK-mediated cytolysis. Immunol. Today 21, 228 –234. Moretta, L., Biassoni, R., Bottino, C., Mingari, M.C., Moretta, L., 2000b. Human NK-cell receptors. Immunol. Today 21, 420 – 422. Moretta, A., Bottino, C., Vitale, M., Pende, D., Cantoni, C., Biassoni, R., Mingari, M.C., Moretta, L., 2001. Activating receptors and coreceptors involved in the natural cytotoxicity. Annu. Rev. Immunol. 19, 197 – 223. Murakami, M.S., Ravetch, J.V., 1992. Signal transduction by Fc gamma RIII (CD16) is mediated through the gamma chain. J. Exp. Med. 175, 1381 –1390. Nakajima, H., Cella, M., Langen, H., Friedlein, A., Colonna, M., 1999. Activating interactions in human NK cell recognition: the role of 2B4-CD48. Eur. J. Immunol. 29, 1676 – 1683. Nakajima, H., Cella, M., Bouchon, A., Grierson, H.L., Lewis, J., Duckett, C.S., Cohen, J.I., Colonna, M., 2000. Patients with X-linked lymphoproliferative disease have a defect in 2B4 receptor-mediated NK cell cytotoxicity. Eur. J. Immunol. 30, 3309 – 3318. Nalabolu, S.R., Shukla, H., Nallur, G., Parimoo, S., Weissman, S.M., 1996. Genes in a 220-kb region spanning the TNF cluster in human MHC. Genomics 31, 215 –222. Neville, M.J., Campbell, R.D., 1999. A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC. J. Immunol. 162, 4745 – 4754. Nichols, K.E., Harkin, D.P., Levitz, S., Krainer, M., Kolquist, K.A., Genovese, C., Bernard, A., Ferguson, M., Zuo, L., Snyder, E., Buckler, A.J., Wise, C., Ashley, J., Lovett, M., Valentine, M.B., Look, A.T., Gerald, W., Housman, D.E., Haber, D.A., 1998. Inactivating mutations in an SH2 domain-encoding gene in Xlinked lymphoproliferative syndrome. Proc. Natl. Acad. Sci. USA 95, 13765 – 13770. Olcese, L., Lang, P., Ve´ ly, F., Cambiaggi, A., Marguet, D., Ble´ ry, M., Hippen, K.L., Biassoni, R., Moretta, A., Moretta, L., Cambier, J.C., Vivier, E., 1996. Human and mouse natural killer cell inhibitory receptors recruit the PTP1C and PTP1D protein tyrosine phosphatases. J. Immunol. 156, 4531 –4534. Olcese, L., Cambiaggi, A., Semenzato, G., Bottino, C., Moretta, A., Vivier, E., 1997. Human killer cell activatory receptors for MHC class I molecules are included in a multimeric complex expressed by natural killer cells. J. Immunol. 158, 5083 – 5086.
1023
Orloff, D.G., Ra, C.S., Frank, S.J., Klausner, R.D., Kinet, J.P., 1990. Family of disulphide-linked dimers containing the zeta and eta chains of the T-cell receptor and the gammachain of Fc receptors. Nature 347, 189 – 191. Parolini, S., Bottino, C., Falco, M., Augugliaro, R., Giliani, S., Franceschini, R., Ochs, H.D., Wolf, H., Bonnefoy, J-Y., Biassoni, R., Moretta, L., Notarangelo, L.D., Moretta, A., 2000. X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of NK cells to kill EBV-infected cells. J. Exp. Med. 192, 337 –346. Pende, D., Biassoni, R., Cantoni, C., Verdiani, S., Falco, M., Di Donato, C., Accame, L., Bottino, C., Moretta, A., Moretta, L., 1996. The natural killer receptor specific for HLA-A allotypes: a novel member of the p58/p70 family of inhibitory receptors that is characterized by three immunoglobulin-like domains and is expressed as a 140 kDa disulphide-linked dimer. J. Exp. Med. 184, 1 – 14. Pende, D., Parolini, S., Pessino, A., Sivori, S., Augugliaro, R., Morelli, L., Marcenaro, E., Accame, L., Malaspina, A., Biassoni, R., Bottino, C., Moretta, L., Moretta, A., 1999. Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J. Exp. Med. 190, 1505 – 1516. Pende, D., Cantoni, C., Rivera, P., Vitale, M., Castriconi, R., Marcenaro, S., Nanni, M., Biassoni, R., Bottino, C., Moretta, A., Moretta, L., 2001. Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin. Eur. J. Immunol. 31, 1076 – 1086. Pessino, A., Sivori, S., Bottino, C., Malaspina, A., Morelli, L., Moretta, L., Biassoni, R., Moretta, A., 1998. Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. J. Exp. Med. 188, 953 – 960. Ploegh, H.L., 1998. Viral strategies of immune evasion. Science 280, 248 – 253. Poy, F., Yaffe, M.B., Sayos, J., Saxena, K., Morra, M., Sumegi, J., Cantley, L.C., Terhorst, C., Eck, M.J., 1999. Crystal structure of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition. Mol. Cell. 4, 555 – 561. Roda-Navarro, P., Arce, I., Renedo, M., Montgomery, K., Kucherlapati, R., Fernandez-Ruiz, E., 2000. Human KLRF1, a novel member of the killer cell lectin-like receptor gene family: molecular characterization, genomic structure, physical mapping to the NK gene complex and expression analysis. Eur. J. Immunol. 30, 568 – 576. Sayos, J., Wu, C., Morra, M., Wang, N., Zhang, X., Allen, D., van Schaik, S., Notarangelo, L., Geha, R., Roncarolo, M.G., Oettgen, H., De Vries, J.E., Aversa, G., Terhorst, C., 1998. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462 –469. Shibuya, A., Campbell, D., Hannum, C., Yssel, H., Franz-Bacon, K., McClanahan, T., Kitamura, T., Nicholl, J., Sutherland, G.R., Lanier, L.L., Phillips, J.H., 1996. DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 4, 573 – 581. Siliciano, R.F., Pratt, J.C., Schmidt, R.E., Ritz, J., Reinherz, E.L., 1985. Activation of cytolytic T lymphocyte and natural killer cell function through the T11 sheep erythrocyte binding protein. Nature 317, 428 – 430. Sivakamasundari, R., Raghunathan, A., Zhang, C.Y., Chowdhury, R.R., Weissman, S.M., 2000. Expression and cellular localization of the protein encoded by the 1C7 gene: a recently described component of the MHC. Immunogenetics 51, 723 – 732. Sivori, S., Vitale, M., Morelli, L., Sanseverino, L., Augugliaro, R., Bottino, C., Moretta, L., Moretta, A., 1997. p46, a novel natural
1024
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
killer cell-specific surface molecule which mediates cell activation. J. Exp. Med. 186, 1129 –1136. Sivori, S., Pende, D., Bottino, C., Marcenaro, E., Pessino, A., Biassoni, R., Moretta, L., Moretta, A., 1999. NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human natural killer cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells. Eur. J. Immunol. 29, 1656 – 1666. Sivori, S., Parolini, S., Marcenaro, E., Castriconi, R., Pende, D., Millo, R., Moretta, A., 2000a. Involvement of natural cytotoxicity receptors in human natural killer cell mediated lysis of neuroblastoma and glyoblastoma cell lines. J. Neuroimmunol. 107, 220 – 225. Sivori, S., Parolini, S., Falco, M., Marcenaro, E., Biassoni, R., Bottino, C., Moretta, L., Moretta, A., 2000b. 2B4 functions as a co-receptor in human NK cell activation. Eur. J. Immunol. 30, 787 – 793. Tangye, S.G., Lazetic, S., Woollatt, E., Sutherland, G.R., Lanier, L.L., Phillips, J.H., 1999. Human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. J. Immunol. 162, 6981 –6985. Tangye, S.G., Phillips, J.H., Lanier, L.L., 2000a. The CD2-subset of the Ig superfamily of cell surface molecules: receptor-ligand pairs expressed by NK cells and other immune cells. Semin. Immunol. 12, 149 – 157. Tangye, S.G., Phillips, J.H., Lanier, L.L., Nichols, K.E., 2000b. Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. J. Immunol. 165, 2932 –2936.
Trincheri, G., 1990. Biology of natural killer cell. Adv. Immunol. 47, 187 – 376. Valiante, N.M., Trinchieri, G., 1993. Identification of a novel signal transduction surface molecule on human cytotoxic lymphocytes. J. Exp. Med. 178, 1397 – 1406. Vitale, M., Bottino, C., Sivori, S., Sanseverino, L., Castriconi, R., Marcenaro, R., Augugliaro, R., Moretta, L., Moretta, A., 1998. NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells is involved in non-MHC restricted tumor cell lysis. J. Exp. Med. 187, 2065 – 2072. Vitale, M., Falco, M., Castriconi, R., Parolini, S., Zambello, R., Semenzato, G., Biassoni, R., Bottino, C., Moretta, L., Moretta, A., 2001. Identification of NKp80 a novel triggering molecule expressed by human NK cells. Eur. J. Immunol. 31, 233 –242. Wagtmann, N., Biassoni, R., Cantoni, C., Verdiani, S., Malnati, M.S., Vitale, M., Bottino, C., Moretta, L., Moretta, A., Long, E.O., 1995. Molecular clones of the p58 NK cell receptor reveal immunoglobulin related molecules with diversity in both the extra- and intracellular domains. Immunity 2, 439 – 449. Wende, H., Colonna, M., Ziegler, A., Volz, A., 1998. Organization of the leukocyte cluster (LRC) on human chromosome 19q13.4. Mamm. Genome 10, 154 – 160. Wirthmueller, U., Kurosaki, T., Murakami, M.S., Ravetch, J.V., 1992. Signal transduction by Fc gamma RIII (CD16) is mediated through the gamma chain. J. Exp. Med. 175, 1381 – 1390. Wu, J., Song, Y., Bakker, A.B., Bauer, S., Spies, T., Lanier, L.L., Phillips, J.H., 1999. An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285, 730 – 732. Wu, J., Cherwinski, H., Spies, T., Phillips, J.H., Lanier, L.L., 2000. DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in NK cells. J. Exp. Med. 192, 1059 –1067.
Review
Human natural killer cell activating receptors Roberto Biassoni a,*, Claudia Cantoni b,c, Michela Falco b,c, Daniela Pende a, Romano Millo b, Lorenzo Moretta b,c, Cristina Bottino a, Alessandro Moretta b a
Istituto Nazionale per la Ricerca sul Cancro, Laboratorio di Immunologia, IST/CBA, L.go R. Benzi, 10, 16132 Geno6a, Italy b Dipartimento di Medicina Sperimentale, Uni6ersita` degli Studi di Geno6a, Geno6a, Italy c Istituto Giannina Gaslini, Geno6a, Italy Received 13 March 2001; accepted 14 March 2001
Abstract Natural killer (NK) cells were poorly characterized until 10 years ago and few molecules expressed on their cell surface were known. Now the situation has changed dramatically, since a plethora of receptors characterized by opposite functions have been functionally and molecularly defined. NK cells express clonally distributed inhibitory receptors specific for different groups of HLA class I alleles, thus protecting normal cells from NK-mediated lysis. On the contrary, various activating receptors are involved in triggering of NK-mediated natural cytotoxicity. Their engagement induces human NK cells to kill target cells that are either HLA class I-negative or -deficient. Here a brief description of the activating receptors and coreceptor and of their ligand(s) is given. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Receptors; Natural killer; HLA
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1015
2. Activating HLA class I-specific receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1016
3. Natural cytotoxicity receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1017
4. NKG2D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1019
5. Activating coreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1019
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1021
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1021
1. Introduction Natural killer (NK) cells represent a first line of defense of the immune system against transformed and
* Corresponding author. Tel.: + 39-010-5737221; fax: +39-010354123. E-mail address: [email protected] (R. Biassoni).
virally infected cells (Trincheri, 1990; Biron, 1997). In humans, NK cells efficiently lyse abnormal cells that either lack the expression or express inadequate amounts of HLA class I molecules. In this context, it is known that downregulation of HLA class I expression is a frequent event during tumor transformation or following viral infection (Garrido, 1996; Garrido et al., 1997; Ploegh, 1998). The ability of human NK cells to
0161-5890/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 1 6 1 - 5 8 9 0 ( 0 1 ) 0 0 0 1 8 - 9
1016
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
discriminate between normal and HLA class I-deficient cells is due to the expression of clonally distributed HLA class I inhibitory receptors that, upon recruitment of specific phosphatases (SHP-1 and SHP-2) inhibit the NK-mediated cytotoxicity by acting on the triggering signal cascades (Olcese et al., 1996; Burshtyn et al., 1996; Campbell et al., 1996). A common structural feature of all inhibitory receptors is the presence in their intracytoplasmic tails of the Immune Tyrosine Inhibitory Motif (ITIM) sequences (Bolland and Ravetch, 1999). The inhibitory receptors belong to two distinct receptor families, the immunoglobulin superfamily (IgSF) and the C type lectin superfamily (Moretta et al., 1996, 1997; Lanier, 1998a; Long, 1999; Lopez-Botet et al., 1997). The different Killer Inhibitory Receptors (KIR) all belong to the Ig-SF and specifically recognize different groups of HLA class I alleles (Colonna and Samaridis, 1995; D’Andrea et al., 1995; Wagtmann et al., 1995; Pende et al., 1996; Dohring et al., 1996; Moretta et al., 1997). The genes coding for KIR have been mapped on chromosome 19q13.42 in a region called Leukocyte Receptor Complex (LRC) (Wende et al., 1998; Barten et al., 2001). The inhibitory receptor belonging to the C type lectin family is represented by a heterodimeric structure formed by CD94 and NKG2A molecules (Carretero et al., 1997; Lazetic et al., 1996; Brooks et al., 1997; Houchins et al., 1997) displays a specificity for the non classical HLA class I molecule HLA-E (Braud et al., 1998; Borrego et al., 1998; Lee et al., 1998). The CD94/NKG2A encoding genes have been mapped on chromosome 12p12-13 in a region called NK gene complex (Barten et al., 2001). Importantly, the HLA class I specific inhibitory receptors block NK-mediated cytotoxicity by down-regulating the function of different triggering receptors. Several molecules have been identified that are able to trigger NK-mediated cytotoxicity. These include CD16, CD2 and DNAM-1. CD16 (FcgRIII), the low affinity receptor for IgG, is able to transduce activating signals through its association with the g subunit of the high affinity IgE receptor (FcoRIg) and the CD3z subunit (Lanier et al., 1989; Orloff et al., 1990; Wirthmueller et al., 1992; Murakami and Ravetch, 1992). Following CD16 mAb-mediated crosslinking the Immunoreceptor Tyrosine-based Activating Motifs (ITAM) in the cytoplasmic tail of CD3z and FcoRIg molecules are tyrosine phosphorylated by the src family member p56lck and initiate the activating signal cascade. CD16 is involved in the Antibody Dependent Cell-mediated Cytotoxicity (ADCC), while its implication in NK-mediated natural cytotoxicity is still controversial (Mandelboin et al., 1999; Sivori et al., 2000a). CD16 is expressed on the majority of, but not all, human NK cells and on activated monocytes as well as on a T cell subset. CD2 is a 50 kDa surface protein belonging to the Ig-SF (Siliciano et al., 1985; Bolhuis et al., 1986) that is
expressed on a NK cell subset and on all T cells. CD2 engagement results in NK cell activation only in a fraction of CD2+ NK cells thus suggesting that it may function as a co-receptor during natural cytotoxicity. Similar to CD2, DNAM-1 is another broadly expressed surface molecule that has been implicated in cell adhesion (Shibuya et al., 1996). More recently, different NK receptors have been characterized that in most instances display an NK-restricted cell surface distribution and that appear to be directly involved in the initiation of NK-mediated natural cytotoxicity. These include HLA class I-specific and non-HLA class I-specific activating receptors (Biassoni et al., 2001; Moretta et al., 2001).
2. Activating HLA class I-specific receptors Upon ligand recognition these receptors trigger, rather than inhibit, the NK-mediated cytolysis (Moretta et al., 1995). Similar to HLA class I-specific inhibitory receptors, they belong to the Ig-SF or to C type lectin superfamily (Biassoni et al., 1996; Bottino et al., 1996; Cantoni et al., 1998; Houchins et al., 1997; Lanier et al., 1998b). Those belonging to the Ig-SF are represented by p50/KIR2DS molecules (Biassoni et al., 1996; Bottino et al., 1996), while CD94/NKG2C and CD94/NKG2E heterodimers belong to the C-type lectin superfamily (Houchins et al., 1991; Chang et al., 1995) (Fig. 1). These receptors display a high degree of amino acid sequence identity with the corresponding inhibitory ones in their extracellular portions, thus indicating that they may recognize the same groups of HLA class I alleles as their inhibitory counterparts. Indeed, this has been demonstrated both at the functional and at the molecular level for p50.1/KIR2DS1, p50.2/KIR2DS2 and CD94/NKG2C (Biassoni et al., 1996, 1997; Braud et al., 1998; Borrego et al., 1998; Lee et al., 1998). The functional role of these activating receptors is still debated. It has been suggested that they may recognize ‘unusual’ or ‘non-self’ peptides in the context of HLA class I molecules. On the other hand, it is also possible that they may be involved in killing of HLA class I positive target cells that have undergone cell surface downregulation of protective alleles (Moretta et al., 2001). HLA class I-specific activating receptors display some common structural features (Biassoni et al., 1996). Thus, different from their inhibitory counterparts, the cytoplasmic tail of activating receptors does not contain ITIM sequences, whereas a charged residue (lysine) characterizes the transmembrane portion. This residue is involved in the association of activating receptors with the ITAM-containing KARAP/DAP12 molecules that are involved in the transduction of activating signals (Olcese et al., 1997; Lanier et al., 1998c; Bottino et al., 2000a; Campbell et al., 1998; Lanier et
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
al., 1998b). It is of note that the gene coding for KARAP/DAP12 has been mapped on chromosome 19q centromeric to KIR genes (Barten et al., 2001). Although these triggering receptors are able to initiate NK cell activation and target cell lysis, they clearly cannot be responsible for natural cytotoxicity against HLA class I-negative target cells. This indicates the existence of additional triggering NK receptors able to recognize non-HLA class I ligands on target cells. Some of these receptors have been recently identified and collectively termed Natural Cytotoxicity Receptors (NCR) (Moretta et al., 2000a,b, 2001; Bottino et al., 2000b; Biassoni et al., 2001)
3. Natural cytotoxicity receptors The common characteristics of NCR are their selective expression on NK cells and their ability to induce NK cell triggering in a HLA class I-independent fashion. Moreover, mAb-mediated interference of NCR/ligand recognition results in the inhibition of natural cytotoxicity. Another important feature is that under physiological conditions (i.e. against autologous HLA class I+ target cells), the NK cell activation induced via NCR is negatively regulated by HLA class I-specific receptors. It is of note that NCR identified so far are able to play either a cooperative or a synergistic role in the activation of NK-mediated cytolysis against different types of tumor target cells. This demonstrates that
1017
natural cytotoxicity is the result of multiple receptor/ ligand interactions between NK and target cells (Moretta et al., 2000a,b, 2001). So far three different NCR, NKp46, NKp30 and NKp44, have been characterized, both at the functional and at the molecular level (Fig. 2). NKp46, the first NCR identified, is selectively expressed by all resting and activated NK cells (Sivori et al., 1997). It represents the main receptor responsible for natural cytotoxicity and its mAb-mediated crosslinking also induces Ca++ mobilization and cytokine release. NKp46 is involved in lysis of different target cells, including both normal and tumor cells of autologous, allogeneic or xenogeneic origin (Sivori et al., 1999). In particular, it was found to be implicated in the NK-mediated lysis of the majority of human tumors belonging to different histotypes, including lung, liver, breast carcinoma, melanoma and EBV-infected cell lines. The surface density of NKp46 may differ in different NK cells or in different individuals. Importantly, the magnitude of NK-mediated cytolytic activity correlate with the level of NKp46 surface expression, indicating that NKp46 plays a key role in natural cytotoxicity (Sivori et al., 1999). A recent report shows that NKp46 is able to recognize in a sialic acid-dependent manner viral ligands, such as haemagglutinin of influenza virus or haemagglutinin–neuraminidase of parainfluenza virus (Mandelboim et al., 2001). It is of note, however, that most target cells that are killed via NKp46 do not express these ligands. This indicates that NKp46 recog-
Fig. 1. HLA class I-specific activating receptors. Receptors specific for two distinct group of HLA-C class I alleles belongs to the Ig-SF. Their transmembrane portion, display the positively charged amino acid lisine that is involved in the association with KARAP/DAP12 ITAM-bearing signal-transducing molecules. In particular, p50.1/KIR2DS1 receptor recognizes HLA-Cw4 and other HLA-C alleles sharing Asn (N) 77 and Lys (K) 80, while p50.2/KIR2DS2 is specific for HLA-Cw3 and related HLA-C alleles sharing Ser (S) 77 and Asn (N) 80 in the a1 domain of the heavy chain, as shown. CD94/NKG2-C and -E belongs to the C type lectin family of receptors and display HLA-E specificity.
1018
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
Fig. 2. Molecular structure of NCR (NKp46, NKp44, NKp30) and NKG2D and their association with distinct signal transducing molecules. NCR belong to the Immunoglobulin superfamily, while NKG2D is a member of the C type lectin receptor family. NKp46 displays an extracellular portion characterized by two Ig-like domains of the C2 type. An extracellular region containing a single Ig-like domain of the V type characterizes NKp30 and NKp44. NCR transmembrane portions contain positively charged amino acids that are supposed to be crucial for their association with distinct signal transducing molecules bearing typical ITAM. NKG2D associate with KAP10/DAP10 polypeptide that upon tyrosine phosphorylation recruits phosphatidylinositol 3-kinase. Putative N-linked or O-linked glycosilation sites are indicated as horizontal or angled lines, respectively.
nize on target cells additional still undefined ligands that are likely to play a major role in NK-cell activation via this receptor. NKp46 is a glycoprotein belonging to the Ig-SF characterized by two extracellular Ig-like domains of the C2 type (Pessino et al., 1998). The transmembrane region contains an arginine residue possibly involved in the association of NKp46 with the ITAM-bearing molecules CD3z and FcoRIg. These associated polypeptides are involved in the signal transduction initiated by NKp46 receptor. The gene coding for NKp46 has been mapped on chromosome 19 (Pessino et al., 1998) in the LRC region, just telomeric to the FcaR (CD89), whereas the KIR multigene family is located centromeric to the FcaR gene (Barten et al., 2001). The NKp46 locus is also conserved in rodents (both mouse and rat) (Biassoni et al., 1999; Falco et al., 1999) and in non human primates such as Macaca fascicularis (De Maria et al., 2001). In accordance with the ability of human NKp46 to recognize murine target cells, a murine homologue of NKp46 has been isolated and cloned, suggesting a possible conservation of NKp46 function during evolution. Moreover, the macaque NKp46 was found to share both function and cellular distribution with its human counterpart (De Maria et al., 2001). NKp30 shares some common features with NKp46. In particular, NKp30 is selectively expressed by all NK cells either resting or activated, and mAb-mediated crosslinking induces Ca++ flux, cytotoxicity and cytokine production (Pende et al., 1999). NKp30 is a 30 kDa glycoprotein belonging to the Ig-SF, that displays a single extracellular IgV domain and a transmembrane portion characterized by an arginine residue (Pende et al., 1999). NKp30 transduces activating signals via the
association with the CD3z chain. Molecular cloning revealed the identity of NKp30 cDNA with the 1C7 gene (Nalabolu et al., 1996; Neville and Campbell, 1999; Sivakamasundari et al., 2000). The latter was mapped on chromosome 6p at the telomeric end of the HLA class III region between the LTB (lymphotoxin beta or TNF superfamily member 3) and AIF1 (allograft inflammatory factor 1) genes (Neville and Campbell, 1999). In M. fascicularis, a gene has been identified that encodes a functional NKp30 receptor (De Maria et al., 2001), while in the mouse only a NKp30 pseudogene has been identified so far (Sivakamasundari et al., 2000). Altogether these data suggest that NKp30 gene may have appeared more recently than NKp46 in evolution. Different from NKp46 and NKp30 receptors, NKp44 is selectively expressed by interleukin-2 (IL-2) cultured NK cells, thus representing the first marker for the identification of activated NK cells (Vitale et al., 1998). This suggests that NKp44 may be, at least in part, responsible for the enhanced cytolytic activity of activated NK cells as compared with freshly isolated NK lymphocytes (Grimm, 1982; Ferrini et al., 1987). NKp44 is another member of the Ig-SF characterized, as NKp30, by a single extracellular Ig V domain (Cantoni et al., 1999). The transmembrane portion contains the charged lysine residue possibly involved in NKp44 association with KARAP/DAP12 polypeptides. These ITAM-containing molecules are necessary both for the surface expression of NKp44 and for transducing activating signals. The NKp44 gene maps on chromosome 6, 120 and 180 kb from the TREM-1 (triggering receptor expressed on myeloid cells-1) and TREM-2 genes. TREM genes encode two novel KARAP/DAP12-associated receptors expressed either on neutrophils and
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
monocytes (TREM-1) or on macrophages and dendritic cells (TREM-2) (Bouchon et al., 2000). At variance with the other NCR, NKp44 gene has not been identified so far in species different from humans. There is a coordinated surface expression of the three NCR, thus it is possible to identify NK clones with NCRbright or NCRdull phenotype (Pende et al., 1999; Sivori et al., 1999, 2000a). The cellular ligands of NCR have not yet been characterized. The functional data indicate that such ligands appear to be expressed on both normal and tumor cells. However, it is possible that their expression may vary following cellular stress, cellular activation or tumor transformation. It is of note that some tumor cells seem to lack certain NCR ligands. This suggests the existence of an in vivo mechanism of tumor escape from NK-mediated recognition based on the downregulation of NCR-specific ligand molecules. Since NCR play a major role in the induction of natural cytotoxicity, the characterization of their ligands will be important for tumor cell typing as well as for novel immunotherapy approaches.
4. NKG2D NKG2D is a member of the C-type lectin superfamily (Wu et al., 1999; Bauer et al., 1999) that is only distantly related to the other members of the NKG2 family (Houchins et al., 1991) and does not associate with CD94, being expressed as a homodimer (Wu et al., 1999). Its function and expression depend upon the association with a newly identified signaling subunit, termed DAP10 (Wu et al., 1999) or KAP10 (Chang et al., 1999) (Fig. 2). DAP10/KAP10 upon tyrosine phosphorylation recruits phosphatidylinositol 3-kinase (Wu et al., 1999; Chang et al., 1999; Wu et al., 2000). Gene coding for this transducing polypeptide has been mapped on chromosome 19q just telomeric to KARAP/ DAP12 gene (Barten et al., 2001). Different from NCR, NKG2D expression is not confined to NK cells, since it is also expressed by virtually all TCR g/d+ and CD8+ TCR a/b+ cells. In NK cell clones, NKG2D was found to complement the role of NCR in tumor cell lysis (Pende et al., 2001). Thus, available data suggest that NK cell triggering in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. The first identified ligands recognized by NKG2D were the stress-inducible molecules MICA and MICB (Groh et al., 1996, 1999; Bauer et al., 1999) that are encoded within the human MHC complex. These molecules have been first described on epithelial tumors (Groh et al., 1999), but also other tumor cell lines (i.e. melanomas) were found to be MICA+ (Pende et al., 2001). Recently, ULBP (UL16 binding proteins) have been described as additional NKG2D ligands, ex-
1019
pressed in a variety of cells and tissues (Cosman et al., 2001). On the other hand, still undefined additional ligands may exist, since MICA−/B− ULBP− cells (i.e. Daudi cell line and PHA blasts) appeared to be lysed in a NKG2D-dependent manner. NK cell triggering via NKG2D has been shown to override the negative signaling generated by the engagement of HLA class I-specific inhibitory receptors (Bauer et al., 1999). On the contrary, a recent report showed that, similar to NCR, the NKG2D-mediated cytolytic activity is under the control of HLA class I inhibitory receptors. Indeed, NKG2D-mediated activation of NK cells could be strongly inhibited by the simultaneous engagement of NKG2D and KIR by specific mAbs or by MICA and HLA class I molecules expressed on target cells (Pende et al., 2001).
5. Activating coreceptors Other surface molecules participate in the induction of NK cell triggering against certain target cell types. One of these molecules is represented by 2B4 (CD244) (Fig. 3). 2B4 is expressed by virtually all NK cells (resting and IL2 cultured) and by monocytes, basophils and a CD8+ T cells subset (Nakajima et al., 1999). The natural ligand of 2B4 is CD48 molecule expressed on the cell surface of T, B (fresh and EBV transformed), NK cells, monocytes and endothelial cells (Latchman et al., 1998; Brown et al., 1998; Kubin et al., 1999). 2B4 induces NK cell activation as demonstrated by the use of anti-2B4 mAb in redirected killing assay against FcgR+ murine targets (Moretta et al., 1992; Valiante and Trinchieri, 1993). However, analysis at clonal level revealed that this effect was confined to NK cells expressing high NCR surface densities. This suggested that the engagement of NKp46 (by ligand expressed on murine targets) may provide the first signal necessary for the subsequent responsiveness to 2B4 engagement by specific mAb or by the specific ligand (CD48) expressed on target cells. This supported the notion that 2B4 acts as a coreceptor during natural cytotoxicity against CD48+ targets (Sivori et al., 2000b). Structurally, 2B4 is a type I transmembrane protein (Latchman et al., 1998; Tangye et al., 1999; Boles et al., 1999; Kubin et al., 1999) belonging to the CD2 subfamily, which includes CD48, CD58, CD84, CD150 (also termed SLAM) and Ly9. All the CD2 subfamily genes have been located in two clusters on chromosome 1, in particular CD2 and CD58 are located at 1p13.1 whereas Ly9, CD48 and 2B4 at 1q21-23 (Tangye et al., 2000a). These genes are likely to have arisen in a series of gene duplication events, and duplication of the entire chromosomal region is likely to have given two pericentric regions. The extracellular portions of the CD2 subfamily members display similar structure being com-
1020
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
posed of a N terminal non-disulfide bonded V domain and a membrane-proximal C2 domain, the only exception being represented by Ly9 that shows two V-C2 modules. On the other hand, the cytoplasmic tails of the various members of this family are heterogeneous. CD48 is a GPI-linked surface molecule, whereas alter-
Fig. 3. Molecular structure of activating coreceptors. 2B4 is a type I transmembrane protein belonging to the CD2 subfamily, which includes CD48, CD58, CD84, CD150 and Ly9. 2B4 cytoplasmic region contains four tyrosine-based motifs characterized by the TxYxxV/I consensus sequence, implicated in the association with a small cytoplasmic polypeptide termed Src homology 2 domain-containing protein (SH2D1A) (or SLAM-associated protein SAP) and with SHP phosphatases. NKp80 is a type II transmembrane protein belonging to the C type lectin superfamily.
natively spliced forms of CD58 give rise to either a transmembrane form with a short (12 amino acid) cytoplasmic tail or a GPI-anchored protein. CD2, CD84, CD150, 2B4 and Ly9 are characterized by tails of different length (70–180 amino acids). Importantly, CD150, CD84, Ly9 and 2B4 cytoplasmic regions contain two or more tyrosine-based motifs characterized by the TxYxxV/I consensus sequence. Recently, this motif has been implicated in the association with a small cytoplasmic polypeptide termed Src homology 2 domain-containing protein (SH2D1A) (or SLAM-associated protein SAP) (Poy et al., 1999). The signal transducing pathway initiated via 2B4 has been recently clarified. 2B4 lacks both ITAM sequence in the cytoplasmic tail and charged amino acids in the transmembrane portion. In agreement with the latter finding, no association with ITAM-bearing polypeptides could be detected. On the other hand, it has been demonstrated that in human NK cells 2B4 associates with SHP-1 and that cell treatment with sodium pervanadate leads phosphorylation of 2B4 and its consequent association with SH2D1A. These results suggested that SH2D1A may sustain the 2B4-mediated triggering response by preventing the generation of inhibitory signals mediated by SHP-1 (Parolini et al., 2000). Along this line, it has been demonstrated that in NK cells derived from patients affected by X-linked lymphoproliferative (XLP) disease 2B4 displays a dramatically altered function. XLP patients are characterized by critical mutations in the SH2D1A encoding gene (Sayos et al., 1998; Coffey et al., 1998; Nichols et al., 1998). Due to the absence of a functional SH2D1A protein 2B4 engagement by the specific ligand (CD48), expressed at high densities on EBV infected cells, results in inhibitory rather than activating signals (Parolini et al., 2000; Benoit et al., 2000; Nakajima et al., 2000; Tangye et al., 2000b). This may provide a possible explanation of the inefficient control of EBV infection in XLP patients. A recent study demonstrated that 2B4 is constitutively associated with the linker for the activation of T cells (LAT). Indeed, antibody-mediated engagement of 2B4 resulted in tyrosine phosphorylation of 2B4 and of the associated LAT molecules. Tyrosine phosphorylation of LAT leads in turn to the recruitment of cytoplasmic signaling molecules, such as PLCg and Grb2 (Bottino et al., 2000c). A novel triggering molecule has been recently characterized at the functional, biochemical and molecular level. This molecule, termed NKp80 (Vitale et al., 2001), is expressed by all NK cells (fresh and activated) and by a small CD56+ T cell subset (Fig. 3). Functional studies revealed that NK cells display a marked heterogeneity in the magnitude of cytolytic responses to anti NKp80 mAb and that, as earlier demonstrated for 2B4, this correlates with the NKp46 surface density. This data lead to the conclusion that also NKp80 may
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
function as a coreceptor in NK cell mediated cytotoxicity. Molecular cloning revealed that NKp80 is a type II transmembrane protein belonging to the C type lectin superfamily. Although the activating signaling pathway initiated via NKp80 is still undefined, the lack of charged amino acid in the transmembrane region suggests that NKp80 does not transduce signals via the association with ITAM bearing polypeptides such as CD3z, FcoRIg, DAP10 and DAP12. It is possible, however, that the two tyrosine-based motifs (not belonging to typical ITAM sequences) present in the NKp80 cytoplasmic tail, may play a role in the NKp80mediated signaling. Comparison of the cDNA coding for NKp80 in GenBank database revealed its identity with the recently identified KLRF1 cDNA (RodaNavarro et al., 2000). The KLRF1 gene has been mapped in the NKC on chromosome 12p12-p13 telomeric to CD94 and centromeric to AICL. NKp80 ligand(s) is still unknown. Functional studies demonstrated that this receptor cooperates with NCR in the lysis of PHA blasts while does not appear to be involved in the NK-mediated killing of various tumor cells including T cell leukemias. Taken together, these data suggest that NKp80-specific ligand(s) may be either restricted to certain cell types or lost during tumor transformation.
Acknowledgements This work was supported by grants awarded by Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.), Istituto Superiore di Sanita` (I.S.S.), Ministero della Sanita`, and Ministero dell’Universita` e della Ricerca Scientifica e Tecnologica (M.U.R.S.T.) and Consiglio Nazionale delle Ricerche, Progetto Finalizzato Biotecnologie. The financial support of TelethonItaly (grant no.E.0892) is gratefully acknowledged.
References Bauer, S., Groh, V., Wu, J., Steinle, A., Phillips, J.H., Lanier, L.L., Spies, T., 1999. Activation of NK cells and T cells by NKG2D a receptor for stress-inducible MICA. Science 285, 727 – 729. Barten, R., Torkar, M., Haude, A., Trowsdale, J., Wilson, M.J., 2001. Divergent and convergent evolution of NK-cell receptors. Trends Immunol. 22, 52 –57. Benoit, L., Wang, X., Pabst, H.F., Dutz, J., Tan, R., 2000. Defective NK cell activation in X-linked lymphoproliferative disease. J. Immunol. 165, 3549 –3553. Biassoni, R., Cantoni, C., Falco, M., Verdiani, S., Bottino, C., Vitale, M., Conte, R., Poggi, A., Moretta, A., Moretta, L., 1996. The HLA.C specific ‘activatory’ and ‘inhibitory’ natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions. J. Exp. Med. 183, 645 –650.
1021
Biassoni, R., Pessino, A., Malaspina, A., Cantoni, C., Bottino, C., Sivori, S., Moretta, L., Moretta, A., 1997. Role of amino acid position 70 in the binding affinity of p50.1 and p58.1 receptors for Cw4 molecules. Eur. J. Immunol. 27, 3095 – 3099. Biassoni, R., Pessino, A., Bottino, C., Pende, D., Moretta, L., Moretta, A., 1999. The murine homologue of the human NKp46 a triggering receptor involved in the induction of natural cytotoxicity. Eur. J. Immunol. 29, 1014 – 1020. Biassoni, R., Cantoni, C., Pende, D., Sivori, S., Parolini, S., Vitale, M., Bottino C., Moretta, A., 2001. Human natural killer cell receptors and coreceptors. Immunol. Rev., in press. Biron, C.A., 1997. Activation and function of natural killer cell responses during viral infections. Curr. Opin. Immunol. 9, 24 –34. Boles, K.S., Nakajima, H., Colonna, M., Chuang, S.S., Stepp, S.E., Bennett, M., Kumar, V., Mathew, P.A., 1999. Molecular cloning of a novel natural killer cell receptor homologous to mouse 2B4. Tissue Antigens 54, 27 – 34. Bolhuis, R.L., Roozemond, R.C., Van de Griend, R.J., 1986. Induction and blocking of cytolysis in CD2 +, CD3− NK and CD2+ , CD3+ cytotoxic T lymphocytes via CD2 50 kDa sheep erythrocyte receptor. J. Immunol. 136, 3939 – 3944. Bolland, S., Ravetch, J.V., 1999. Inhibitory pathways triggered by ITIM-containing receptors. Adv. Immunol. 72, 149 – 177. Borrego, F., Ulbrecht, M., Weiss, E.H., Coligan, J.E., Brooks, A.G., 1998. Recognition of Human Histocompatibility Leukocyte Antigen (HLA)-E complexed with HLA class I signal sequencederived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J. Exp. Med. 187, 813 – 818. Bottino, C., Sivori, S., Vitale, M., Cantoni, C., Falco, M., Pende, D., Morelli, L., Augugliaro, R., Semenzato, G., Biassoni, R., Moretta, L., Moretta, A., 1996. A novel surface molecule homologous to the p58/p50 family of receptors is selectively expressed on a subset of human natural killer cells and induces both triggering of cell functions and proliferation. Eur. J. Immunol. 26, 1816 – 1824. Bottino, C., Falco, M., Sivori, S., Moretta, L., Moretta, A., Biassoni, R., 2000a. Identification of natural p50.2/KIR2DS mutants unable to transduce activating signals. Eur. J. Immunol. 30, 3569 – 3574. Bottino, C., Biassoni, R., Millo, R., Moretta, L., Moretta, A., 2000b. The human natural cytotoxicity receptors (NCR) that induce HLA class I-independent NK cell triggering. Human Immunol. 61, 1 – 6. Bottino, C., Augugliaro, R., Castriconi, R., Nanni, M., Biassoni, R., Moretta, L., Moretta, A., 2000c. Analysis of the molecular mechanism involved in 2B4-mediated NK cell activation: evidence that human 2B4 is physically and functionally associated with the linker for activation of T cells. Eur. J. Immunol. 30, 3718 –3722. Bouchon, A., Dietrich, J., Colonna, M., 2000. Inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J. Immunol. 164, 4991 – 4995. Braud, V.M., Allan, D.S.J., O’Callaghan, C.A., Soderstrom, K., D’Andrea, A., Ogg, G.S., Lazetic, S., Young, N.T., Bell, J.I., Phillips, J.H., Lanier, L.L., McMichael, A.J., 1998. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795 – 799. Brooks, A.G., Posch, P.E., Scorzelli, C.I., Borrego, F., Coligan, J.E., 1997. NKG2A complexed with CD94 defines a novel inhibitory NK cell receptor. J. Exp. Med. 185, 795 – 800. Brown, M.H., Boles, K., van der Merwe, P.A., Kumar, V., Mathew, P.A., Barclay, A.N., 1998. 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. J. Exp. Med. 188, 2083 – 2090. Burshtyn, D.N., Scharenberg, A.M., Wagtmann, N., Rajagopalan, S., Berrada, K., Yi, T., Kinet, J.P., Long, E.O., 1996. Recruitment of tyrosine phosphatase HCP by the killer cell inhibitory receptor. Immunity 4, 77 – 85.
1022
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
Campbell, K.S., Dessing, M., Lopez-Botet, M., Cella, M., Colonna, M., 1996. Tyrosine phosphorilation of a human killer inhibitory receptor recruits protein phosphatase 1C. J. Exp. Med. 184, 93– 100. Campbell, K.S., Cella, M., Carretero, M., Lopez-Botet, M., Colonna, M., 1998. Signaling through human killer cell activating receptors triggers tyrosine phosphorylation of an associated protein complex. Eur. J. Immunol. 28, 599 –609. Cantoni, C., Biassoni, R., Pende, D., Sivori, S., Accame, L., Pareti, L., Semenzato, G., Moretta, L., Moretta, A., Bottino, C., 1998. The activating form of CD94 receptor complex. CD94 covalently associates with the Kp39 protein that represents the product of the NKG2-C gene. Eur. J. Immunol. 28, 327 – 338. Cantoni, C., Bottino, C., Vitale, M., Pessino, A., Augugliaro, R., Malaspina, A., Parolini, S., Moretta, L., Moretta, A., Biassoni, R., 1999. NKp44, a triggering receptor involved in tumor cell lysis by activated human natural killer cells, is a novel member of the immunoglobulin superfamily. J. Exp. Med. 189, 787 –796. Carretero, M., Cantoni, C., Bello´ n, T., Bottino, C., Biassoni, R., Rodrı´guez, A., Pe´ rez-Villar, J.J., Moretta, L., Moretta, A., Lo´ pezBotet, M., 1997. The CD94 and NKG2-A C-type lectins covalently assamble to form a NK cell inhibitory receptor for HLA class I molecules. Eur. J. Immunol. 27, 563 – 567. Chang, C., Rodriguez, A., Carretero, M., Lopez-Botet, M., Phillips, J.H., Lanier, L.L., 1995. Molecular characterization of human CD94: a type II membrane glycoprotein related to the C-type lectin superfamily. Eur. J. Immunol. 25, 2433 – 2437. Chang, C., Dietrich, J., Harpur, A.G., Lindquist, J.A., Haude, A., Loke, Y.W., King, A., Colonna, M., Trowsdale, J., Wilson, M.J., 1999. KAP10, a novel transmembrane adapter protein genetically linked to DAP12 but with unique signaling properties. J. Immunol. 163, 4651 – 4654. Coffey, A.J., Brooksbank, R.A., Brandau, O., Oohashi, T., Howell, G.R., Bye, J.M., Cahn, A.P., Durham, J., Heath, P., Wray, P., Pavitt, R., Wilkinson, J., Leversha, M., Huckle, E., Shaw-Smith, C.J., Dunham, A., Rhodes, S., Schuster, V., Porta, G., Yin, L., Serafini, P., Sylla, B., Zollo, M., Franco, B., Bolino, A., Seri, M., Lanyi, A., Davis, J.R., Webster, D., Harris, A., Lenoir, G., de St Basile, G., Jones, A., Behloradsky, B.H., Achatz, H., Murken, J., Fassler, R., Sumegi, J., Romeo, G., Vaudin, M., Ross, M.T., Meindl, A., Bentley, D.R., 1998. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat. Genet. 20, 129 – 135. Colonna, M., Samaridis, J., 1995. Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by Human natural killer cells. Science 268, 405 –408. Cosman, D., Mullberg, J., Sutherland, C.L., Chin, W., Armitage, R., Fanslow, W., Kubin, M., Chalupny, N.J., 2001. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14, 123 – 133. D’Andrea, A., Chang, C., Franz-Bacon, K., McClanahan, T., Phillips, J.H., Lanier, L.L., 1995. Molecular cloning of NKB1. A natural killer cell receptor for HLA-B allotypes. J. Immunol. 155, 2306 – 2310. De Maria, A., Biassoni, R., Fogli, M., Rizzi, M., Cantoni, C., Conte, R., Costa, P., Mavilio, D., Cafaro, A., Moretta, A., Moretta, L., 2001. Identification, molecular cloning and functional characterization of NKp46 and NKp30 Natural Cytotoxicity Receptors in Macaca fascicularis (Macaca Rhesus) NK cells. (submitted) Dohring, C., Scheidegger, D., Samaridis, J., Cella, M., Colonna, M., 1996. A human killer inhibitory receptor specific for HLA-A. J. Immunol. 156, 3098 –3101. Falco, M., Cantoni, C., Bottino, C., Moretta, A., Biassoni, R., 1999. Identification of the rat homologue of the human NKp46 triggering receptor. Immunol. Lett. 68, 411 –414.
Ferrini, S., Miescher, S., Zocchi, M.R., Von Fliedner, V., Moretta, A., 1987. Phenotypic and functional characterization of recombinant interleukin-2 (rIL-2)-induced killer cells: analysis at the population and the clonal level. J. Immunol. 138, 1297 –1302. Garrido, F., 1996. MHC molecules in normal and neoplastic cells. Int. J. Cancer 6, 1 – 10. Garrido, F., Ruiz-Cabello, F., Cabrera, T., Pe´ rez-Villar, J.J., Lo`pezBotet, M., Duggan-Keen, M., Stern, P.L., 1997. Implications for immunosurveillance of altered HLA-class I phenotypes in human tumours. Immunol. Today 18, 89 – 95. Grimm, E., 1982. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin-2-activated autologous human peripheral blood lymphocytes. J. Exp. Med. 155, 1823 – 1841. Groh, V., Bahram, S., Bauer, S., Herman, A., Beauchamp, M., Spies, T., 1996. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc. Natl. Acad. Sci. USA 93, 12445 – 12450. Groh, V., Rhinehart, R., Secrist, H., Bauer, S., Grabstein, K.H., Spies, T., 1999. Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc. Natl. Acad. Sci. USA 96, 6879 – 6884. Houchins, J.P., Yabe, T., McSherry, C., Bach, F.H., 1991. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. J. Exp. Med. 173, 1017 – 1020. Houchins, J.P., Lanier, L.L., Niemi, E., Phillips, J.H., Ryan, J.C., 1997. Natural killer cell cytolytic activity is inhibited by NKG2-A and activated by NKG2-C. J. Immunol. 158, 3603 – 3609. Kubin, M.Z., Parsley, D.L., Din, W., Waugh, J.Y., Davis-Smith, T., Smith, C.A., Macduff, B.M., Armitage, R.J., Chin, W., Cassiano, L., Borges, L., Petersen, M., Trinchieri, G., Goodwing, R.G., 1999. Molecular cloning and biological characterization of NK cell activation-inducing ligand, a counterstructure for CD48. Eur. J. Immunol. 29, 3466 – 3477. Lanier, L.L., 1998a. NK cell receptors. Annu. Rev. Immunol. 16, 359 – 393. Lanier, L.L., Corliss, B., Wu, J., Phillips, J.H., 1998b. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity 8, 693 – 701. Lanier, L.L., Corliss, B.C., Jun, W., Leong, C., Phillips, J.H., 1998c. Immunoreceptor DAP12 bearing a tyrosine-based activation motifs is involved in activating NK cells. Nature 391, 703 –707. Lanier, L.L., Yu, G., Phillips, J.H., 1989. Co-association of CD3 zeta with a receptor (CD16) for IgG Fc on human natural killer cells. Nature 342, 803 – 805. Latchman, Y., McKay, P.F., Reiser, H., 1998. Identification of the 2B4 molecule as a counter-receptor for CD48. J. Immunol. 161, 5809 – 5812. Lazetic, S., Chang, C., Houchins, J.P., Lanier, L.L., Phillips, J.H., 1996. Human Natural killer cell receptors involved in MHC class I recognition are disulphide-linked heterodimers of CD94 and NKG2 subunits. J. Immunol. 157, 4741 – 4745. Lee, N., Llano, M., Carretero, M., Ishitani, A., Navarro, F., Lo`pezBotet, M., Gherarty, D., 1998. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc. Natl. Acad. Sci. USA 95, 5199 – 5204. Long, E.O., 1999. Regulation of immune responses through inhibitory receptors. Annu. Rev. Immunol. 17, 875 – 904. Lopez-Botet, M., Pe´ rez-Villar, M., Carretero, A., Rodrı`guez, I., Melero, I., Bellon, T., Llano, M., Navarro, F., 1997. Structure and function of the CD94 C-type lectin receptor complex involved in the recognition of HLA class I molecules. Immunol. Rev. 155, 165 – 174. Mandelboin, O., Malik, P., Davis, D.M., Jo, C.H., Boyson, J.E., Strominger, J.L., 1999. Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity. Proc. Natl. Acad. Sci. USA 96, 5640 – 5644.
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024 Mandelboim, O., Lieberman, N., Lev, M., Paul, L., Arnon, T.I., Bushkin, Y., Davis, D.M., Strominger, J.L., Yewdell, J.W., Porgador, A., 2001. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409, 1055 – 1060. Moretta, A., Bottino, C., Tripodi, G., Vitale, M., Pende, D., Morelli, L., Augugliaro, R., Barbaresi, M., Ciccone, E., Millo, R., Moretta, L., 1992. Novel surface molecules involved in human NK cell activation and triggering of the lytic machinery. Int. J. Cancer Suppl. 7, 6 – 10. Moretta, A., Sivori, S., Vitale, M., Pende, D., Morelli, L., Augugliaro, R., Bottino, C., Moretta, L., 1995. Existence of both inhibitory (p58) and activatory (p50) receptors for HLA.C molecules in human natural killer cells. J. Exp. Med. 182, 875 – 884. Moretta, A., Bottino, C., Vitale, M., Pende, D., Biassoni, R., Mingari, M.C., Moretta, L., 1996. Receptors for HLA-class I molecules in human natural killer cells. Annu. Rev. Immunol. 14, 619 – 648. Moretta, A., Biassoni, R., Bottino, C., Pende, D., Vitale, M., Poggi, A., Mingari, M.C., Moretta, L., 1997. Major histocompatibility complex class I-specifc receptors on human natural killer and T lymphocytes. Immunol. Rev. 155, 105 –117. Moretta, A., Biassoni, R., Bottino, C., Mingari, M.C., Moretta, L., 2000a. Natural cytotoxicity receptors that trigger human NK-mediated cytolysis. Immunol. Today 21, 228 –234. Moretta, L., Biassoni, R., Bottino, C., Mingari, M.C., Moretta, L., 2000b. Human NK-cell receptors. Immunol. Today 21, 420 – 422. Moretta, A., Bottino, C., Vitale, M., Pende, D., Cantoni, C., Biassoni, R., Mingari, M.C., Moretta, L., 2001. Activating receptors and coreceptors involved in the natural cytotoxicity. Annu. Rev. Immunol. 19, 197 – 223. Murakami, M.S., Ravetch, J.V., 1992. Signal transduction by Fc gamma RIII (CD16) is mediated through the gamma chain. J. Exp. Med. 175, 1381 –1390. Nakajima, H., Cella, M., Langen, H., Friedlein, A., Colonna, M., 1999. Activating interactions in human NK cell recognition: the role of 2B4-CD48. Eur. J. Immunol. 29, 1676 – 1683. Nakajima, H., Cella, M., Bouchon, A., Grierson, H.L., Lewis, J., Duckett, C.S., Cohen, J.I., Colonna, M., 2000. Patients with X-linked lymphoproliferative disease have a defect in 2B4 receptor-mediated NK cell cytotoxicity. Eur. J. Immunol. 30, 3309 – 3318. Nalabolu, S.R., Shukla, H., Nallur, G., Parimoo, S., Weissman, S.M., 1996. Genes in a 220-kb region spanning the TNF cluster in human MHC. Genomics 31, 215 –222. Neville, M.J., Campbell, R.D., 1999. A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC. J. Immunol. 162, 4745 – 4754. Nichols, K.E., Harkin, D.P., Levitz, S., Krainer, M., Kolquist, K.A., Genovese, C., Bernard, A., Ferguson, M., Zuo, L., Snyder, E., Buckler, A.J., Wise, C., Ashley, J., Lovett, M., Valentine, M.B., Look, A.T., Gerald, W., Housman, D.E., Haber, D.A., 1998. Inactivating mutations in an SH2 domain-encoding gene in Xlinked lymphoproliferative syndrome. Proc. Natl. Acad. Sci. USA 95, 13765 – 13770. Olcese, L., Lang, P., Ve´ ly, F., Cambiaggi, A., Marguet, D., Ble´ ry, M., Hippen, K.L., Biassoni, R., Moretta, A., Moretta, L., Cambier, J.C., Vivier, E., 1996. Human and mouse natural killer cell inhibitory receptors recruit the PTP1C and PTP1D protein tyrosine phosphatases. J. Immunol. 156, 4531 –4534. Olcese, L., Cambiaggi, A., Semenzato, G., Bottino, C., Moretta, A., Vivier, E., 1997. Human killer cell activatory receptors for MHC class I molecules are included in a multimeric complex expressed by natural killer cells. J. Immunol. 158, 5083 – 5086.
1023
Orloff, D.G., Ra, C.S., Frank, S.J., Klausner, R.D., Kinet, J.P., 1990. Family of disulphide-linked dimers containing the zeta and eta chains of the T-cell receptor and the gammachain of Fc receptors. Nature 347, 189 – 191. Parolini, S., Bottino, C., Falco, M., Augugliaro, R., Giliani, S., Franceschini, R., Ochs, H.D., Wolf, H., Bonnefoy, J-Y., Biassoni, R., Moretta, L., Notarangelo, L.D., Moretta, A., 2000. X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of NK cells to kill EBV-infected cells. J. Exp. Med. 192, 337 –346. Pende, D., Biassoni, R., Cantoni, C., Verdiani, S., Falco, M., Di Donato, C., Accame, L., Bottino, C., Moretta, A., Moretta, L., 1996. The natural killer receptor specific for HLA-A allotypes: a novel member of the p58/p70 family of inhibitory receptors that is characterized by three immunoglobulin-like domains and is expressed as a 140 kDa disulphide-linked dimer. J. Exp. Med. 184, 1 – 14. Pende, D., Parolini, S., Pessino, A., Sivori, S., Augugliaro, R., Morelli, L., Marcenaro, E., Accame, L., Malaspina, A., Biassoni, R., Bottino, C., Moretta, L., Moretta, A., 1999. Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J. Exp. Med. 190, 1505 – 1516. Pende, D., Cantoni, C., Rivera, P., Vitale, M., Castriconi, R., Marcenaro, S., Nanni, M., Biassoni, R., Bottino, C., Moretta, A., Moretta, L., 2001. Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin. Eur. J. Immunol. 31, 1076 – 1086. Pessino, A., Sivori, S., Bottino, C., Malaspina, A., Morelli, L., Moretta, L., Biassoni, R., Moretta, A., 1998. Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. J. Exp. Med. 188, 953 – 960. Ploegh, H.L., 1998. Viral strategies of immune evasion. Science 280, 248 – 253. Poy, F., Yaffe, M.B., Sayos, J., Saxena, K., Morra, M., Sumegi, J., Cantley, L.C., Terhorst, C., Eck, M.J., 1999. Crystal structure of the XLP protein SAP reveal a class of SH2 domains with extended, phosphotyrosine-independent sequence recognition. Mol. Cell. 4, 555 – 561. Roda-Navarro, P., Arce, I., Renedo, M., Montgomery, K., Kucherlapati, R., Fernandez-Ruiz, E., 2000. Human KLRF1, a novel member of the killer cell lectin-like receptor gene family: molecular characterization, genomic structure, physical mapping to the NK gene complex and expression analysis. Eur. J. Immunol. 30, 568 – 576. Sayos, J., Wu, C., Morra, M., Wang, N., Zhang, X., Allen, D., van Schaik, S., Notarangelo, L., Geha, R., Roncarolo, M.G., Oettgen, H., De Vries, J.E., Aversa, G., Terhorst, C., 1998. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462 –469. Shibuya, A., Campbell, D., Hannum, C., Yssel, H., Franz-Bacon, K., McClanahan, T., Kitamura, T., Nicholl, J., Sutherland, G.R., Lanier, L.L., Phillips, J.H., 1996. DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 4, 573 – 581. Siliciano, R.F., Pratt, J.C., Schmidt, R.E., Ritz, J., Reinherz, E.L., 1985. Activation of cytolytic T lymphocyte and natural killer cell function through the T11 sheep erythrocyte binding protein. Nature 317, 428 – 430. Sivakamasundari, R., Raghunathan, A., Zhang, C.Y., Chowdhury, R.R., Weissman, S.M., 2000. Expression and cellular localization of the protein encoded by the 1C7 gene: a recently described component of the MHC. Immunogenetics 51, 723 – 732. Sivori, S., Vitale, M., Morelli, L., Sanseverino, L., Augugliaro, R., Bottino, C., Moretta, L., Moretta, A., 1997. p46, a novel natural
1024
R. Biassoni et al. / Molecular Immunology 37 (2000) 1015–1024
killer cell-specific surface molecule which mediates cell activation. J. Exp. Med. 186, 1129 –1136. Sivori, S., Pende, D., Bottino, C., Marcenaro, E., Pessino, A., Biassoni, R., Moretta, L., Moretta, A., 1999. NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human natural killer cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells. Eur. J. Immunol. 29, 1656 – 1666. Sivori, S., Parolini, S., Marcenaro, E., Castriconi, R., Pende, D., Millo, R., Moretta, A., 2000a. Involvement of natural cytotoxicity receptors in human natural killer cell mediated lysis of neuroblastoma and glyoblastoma cell lines. J. Neuroimmunol. 107, 220 – 225. Sivori, S., Parolini, S., Falco, M., Marcenaro, E., Biassoni, R., Bottino, C., Moretta, L., Moretta, A., 2000b. 2B4 functions as a co-receptor in human NK cell activation. Eur. J. Immunol. 30, 787 – 793. Tangye, S.G., Lazetic, S., Woollatt, E., Sutherland, G.R., Lanier, L.L., Phillips, J.H., 1999. Human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. J. Immunol. 162, 6981 –6985. Tangye, S.G., Phillips, J.H., Lanier, L.L., 2000a. The CD2-subset of the Ig superfamily of cell surface molecules: receptor-ligand pairs expressed by NK cells and other immune cells. Semin. Immunol. 12, 149 – 157. Tangye, S.G., Phillips, J.H., Lanier, L.L., Nichols, K.E., 2000b. Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. J. Immunol. 165, 2932 –2936.
Trincheri, G., 1990. Biology of natural killer cell. Adv. Immunol. 47, 187 – 376. Valiante, N.M., Trinchieri, G., 1993. Identification of a novel signal transduction surface molecule on human cytotoxic lymphocytes. J. Exp. Med. 178, 1397 – 1406. Vitale, M., Bottino, C., Sivori, S., Sanseverino, L., Castriconi, R., Marcenaro, R., Augugliaro, R., Moretta, L., Moretta, A., 1998. NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells is involved in non-MHC restricted tumor cell lysis. J. Exp. Med. 187, 2065 – 2072. Vitale, M., Falco, M., Castriconi, R., Parolini, S., Zambello, R., Semenzato, G., Biassoni, R., Bottino, C., Moretta, L., Moretta, A., 2001. Identification of NKp80 a novel triggering molecule expressed by human NK cells. Eur. J. Immunol. 31, 233 –242. Wagtmann, N., Biassoni, R., Cantoni, C., Verdiani, S., Malnati, M.S., Vitale, M., Bottino, C., Moretta, L., Moretta, A., Long, E.O., 1995. Molecular clones of the p58 NK cell receptor reveal immunoglobulin related molecules with diversity in both the extra- and intracellular domains. Immunity 2, 439 – 449. Wende, H., Colonna, M., Ziegler, A., Volz, A., 1998. Organization of the leukocyte cluster (LRC) on human chromosome 19q13.4. Mamm. Genome 10, 154 – 160. Wirthmueller, U., Kurosaki, T., Murakami, M.S., Ravetch, J.V., 1992. Signal transduction by Fc gamma RIII (CD16) is mediated through the gamma chain. J. Exp. Med. 175, 1381 – 1390. Wu, J., Song, Y., Bakker, A.B., Bauer, S., Spies, T., Lanier, L.L., Phillips, J.H., 1999. An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285, 730 – 732. Wu, J., Cherwinski, H., Spies, T., Phillips, J.H., Lanier, L.L., 2000. DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in NK cells. J. Exp. Med. 192, 1059 –1067.