Cytotoxic Lymphocyte Recognition of HLA-E
1998; Cell Press; Volume: 9; Issue: 3 Linguagem: Inglês
10.1016/s1074-7613(00)80611-1
ISSN1097-4180
Autores Tópico(s)CAR-T cell therapy research
ResumoWhen one tugs at a single thing in nature, he finds it attached to the rest of the world.—John Muir T cell antigen receptors trigger cellular activation after recognition of MHC/peptide complexes. However, structurally distinct MHC-recognizing receptors expressed on natural killer (NK) cells serve an opposite function. Specifically, MHC class I recognition by these novel receptors potently blocks the ability of NK cells to initiate cell-mediated cytotoxicity in vitro or in vivo. Therefore, normal MHC class I–bearing cells are relatively resistant to NK cell–mediated killing because of their ability to engage the NK cell inhibitory receptors. In contrast, malignant or virus-infected cells with reduced MHC class I on their cell surface may fail to engage the NK cell inhibitory receptors and, therefore, can become more susceptible to NK cell–mediated cytotoxicity. As different families of MHC-recognizing receptors on NK cells became molecularly identified and characterized, a paradox emerged. Whereas certain families of these receptors inhibit NK cell activation after directly interacting with classical MHC class I molecules, others seem to sense the presence or absence of classical MHC without clear evidence for a direct interaction. This left unanswered the question as to how certain NK cells can evaluate the expression of classical MHC on potential target cells without bearing receptors capable of binding these molecules. It now appears that the answer to this question has come from an unexpected place. Specifically, recent studies suggest that human NK cells bear inhibitory receptors capable of recognizing the nonclassical MHC molecule HLA-E (6Borrego F Ulbrecht M Weiss E.H Coligan J.E Brooks A.G Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis.J. Exp. Med. 1998; 187: 813-818Crossref PubMed Scopus (555) Google Scholar, 9Braud V.M Allan D.S O'Callaghan C.A Söderström K D'Andrea A Ogg G.S Lazetic S Young N.T Bell J.I Phillips J.H et al.HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.Nature. 1998; 391 (b): 795-799Crossref PubMed Scopus (1596) Google Scholar, 24Lee N Llano M Carretero M Ishitani A Navarro F López-Botet M Geraghty D.E HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A.Proc. Natl. Acad. Sci. USA. 1998; 95 (b): 5199-5204Crossref PubMed Scopus (749) Google Scholar). One of the most striking features about HLA-E is that its predominant ligands are signal sequence–derived peptides from classical MHC class I molecules (7Braud V Jones E.Y McMichael A The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9.Eur. J. Immunol. 1997; 27: 1164-1169Crossref PubMed Scopus (354) Google Scholar). Since HLA-E surface expression depends on the availability of these class I–derived signal sequences (8Braud V.M Allan D.S.J Wilson D McMichael A.J TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide.Curr. Biol. 1998; 8 (a): 1-10Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 23Lee N Goodlett D.R Ishitani A Marquardt H Geraghty D.E HLA-E surface expression depends on binding of TAP-dependent peptides derived from certain HLA class I signal sequences.J. Immunol. 1998; 160 (a): 4951-4960PubMed Google Scholar), immune recognition of HLA-E represents an indirect mechanism for broadly assessing classical MHC class I expression. This review focuses principally on how recognition of HLA-E enables NK cells to monitor the integrity of the MHC class I–dependent antigen presentation pathway. Since certain subpopulations of activated cytotoxic T lymphocytes (CTLs) can also express the HLA-E-recognizing inhibitory receptors, experimental results are described regarding the effects of inhibitory receptors on CTL activation. Finally, the potential implications of HLA-E recognition on antitumor immunity, antiviral immunity, and materno–fetal interactions are discussed. Considerable interest was generated recently by analyses identifying and characterizing novel sets of MHC class I–recognizing receptors expressed on NK cells and subsets of T cells (10Burshtyn D.N Long E.O Regulation through inhibitory receptors lessons from natural killer cells.Trends Cell Biol. 1997; 7: 473-479Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 11Colonna M Specificity and function of immunoglobulin superfamily NK cell inhibitory and stimulatory receptors.Immunol. Rev. 1997; 155: 127-133Crossref PubMed Scopus (104) Google Scholar, 34Moretta A Moretta L HLA class I specific inhibitory receptors.Curr. Opin. Immunol. 1997; 9: 694-701Crossref PubMed Scopus (90) Google Scholar, 49Yokoyama W.M What goes up must come down the emerging spectrum of inhibitory receptors.J. Exp. Med. 1997; 186: 1803-1808Crossref PubMed Scopus (60) Google Scholar, 20Lanier L.L NK cell receptors.Annu. Rev. Immunol. 1998; 16: 359-393Crossref PubMed Scopus (1431) Google Scholar). These molecules provided a mechanistic explanation for how NK cells, a subpopulation of lymphocytes that can kill certain tumor cells, virus-infected cells, and normal hematopoietic cells, can preferentially kill targets lacking self–MHC class I molecules. Specifically, a model emerged in which "class I–bearing targets" versus "class I–deficient targets" have different regulatory effects on NK cell activation (25Ljunggren H.-G Kärre K In search of the "missing self" MHC molecules and NK cell recognition.Immunol. Today. 1990; 11: 237-244Abstract Full Text PDF PubMed Scopus (391) Google Scholar). Class I–bearing targets engage MHC-recognizing inhibitory receptors, resulting in the prevention of NK cell–mediated cytotoxicity. In contrast, class I–deficient targets fail to engage the inhibitory receptors, thus facilitating NK cellular activation and killing. Abundant experimental data from both in vitro and in vivo experimental models support this proposed mechanism and suggest that class I interactions with MHC-recognizing receptors on NK cells critically influence NK cell function. Molecular analyses have identified three distinct types of inhibitory MHC-recognizing receptors on NK cells. First, rodent NK cells express receptors encoded by the small Ly-49 gene family located in a region called the "NK gene complex" on chromosome 6 in mice and on chromosome 4 in rats (50Yokoyama W.M Seaman W.E The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells the NK gene complex.Annu. Rev. Immunol. 1993; 11: 613-635Crossref PubMed Scopus (439) Google Scholar). Ly-49 is a type II integral membrane protein with homology to the C-type lectins. The receptors are expressed as disulfide-linked homodimers, and studies to date suggest that different allelic forms recognize overlapping subsets of class Ia molecules. In addition, Ly-49 gene products are clonally distributed on subpopulations of NK cells, resulting in individual NK cells that may or may not bear the inhibitory receptor for a specific class Ia molecule. However, all murine NK cells are believed to have at least one form of MHC-recognizing inhibitory receptor. Although functional human homologs to murine Ly-49 have not been identified, a putative pseudogene has been located in the human NK cell gene complex on chromosome 12 (p12.3–13.1) (48Westgaard I.H Berg S.F Ørstavik S Fossum S Dissen E Identification of a human member of the Ly-49 multigene family.Eur. J. Immunol. 1998; 28: 1839-1846Crossref PubMed Scopus (97) Google Scholar). Human NK cells express a second type of MHC-recognizing receptor, the human killer cell inhibitory receptors (KIRs) (10Burshtyn D.N Long E.O Regulation through inhibitory receptors lessons from natural killer cells.Trends Cell Biol. 1997; 7: 473-479Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 11Colonna M Specificity and function of immunoglobulin superfamily NK cell inhibitory and stimulatory receptors.Immunol. Rev. 1997; 155: 127-133Crossref PubMed Scopus (104) Google Scholar, 34Moretta A Moretta L HLA class I specific inhibitory receptors.Curr. Opin. Immunol. 1997; 9: 694-701Crossref PubMed Scopus (90) Google Scholar, 20Lanier L.L NK cell receptors.Annu. Rev. Immunol. 1998; 16: 359-393Crossref PubMed Scopus (1431) Google Scholar). KIRs are type I glycoproteins that contain two or three immunoglobulin-like domains in their extracellular regions. Different p58 KIRs, all with two Ig domains, recognize subgroups of HLA-C class I molecules. The p70 KIRs with three Ig domains recognize a subset of HLA-B class I molecules. In addition, a homodimer of two p70 subunits is reported to recognize HLA-A molecules. Like Ly-49 receptors, different KIRs are clonally distributed on subpopulations of NK cells and the repertoire of expressed KIR is heterogeneous in different individuals. A third type of MHC-recognizing inhibitory receptor, best characterized on human NK cells, is CD94/NKG2 (27López-Botet M Perez-Villar J.J Carretero M Rodriguez A Melero I Bellon T Llano M Navarro F Structure and function of the CD94 C-type lectin receptor complex involved in recognition of HLA class I molecules.Immunol. Rev. 1997; 155: 165-174Crossref PubMed Scopus (122) Google Scholar, 20Lanier L.L NK cell receptors.Annu. Rev. Immunol. 1998; 16: 359-393Crossref PubMed Scopus (1431) Google Scholar). This disulfide-linked heterodimer contains two subunits with C-type lectin homology. CD94 appears to be an invariant subunit required for surface expression of NKG2. In contrast, several different NKG2 genes have been identified, with the CD94/NKG2A complex being an identified inhibitory receptor. The CD94 and NKG2 genes are present on human chromosome 12 (p 12.3–13.1) in the human NK gene complex. Rodent CD94 has recently been identified and is located on the syntenic rat chromosome 4 and mouse chromosome 6 (13Dissen E Berg S.F Westgaard I.H Fossum S Molecular characterization of a gene in the rat homologous to human CD94.Eur. J. Immunol. 1997; 27: 2080-2086Crossref PubMed Scopus (61) Google Scholar, 45Vance R.E Tanamachi D.M Hanke T Raulet D.H Cloning of a mouse homolog of CD94 extends the family of C-type lectins on murine natural killer cells.Eur. J. Immunol. 1997; 27: 3236-3241Crossref PubMed Scopus (111) Google Scholar, 17Ho E.L Heusel J.W Brown M.G Matsumoto K Scalzo A.A Yokoyama W.M Murine NKG2D and CD94 are clustered within the natural killer complex and are expressed independently in natural killer cells.Proc. Natl. Acad. Sci. USA. 1998; 95: 6320-6325Crossref PubMed Scopus (113) Google Scholar). The MHC specificity of the CD94/NKG2 complex will be discussed later in this text. Although the three forms of inhibitory MHC-recognizing receptors differ markedly in their extracellular region, the structural basis for their inhibitory activity appears to have been conserved in their cytoplasmic tails (3Binstadt B.A Brumbaugh K.M Leibson P.J Signal transduction by human NK cell MHC-recognizing receptors.Immunol. Rev. 1997; 155: 197-203Crossref PubMed Scopus (39) Google Scholar, 10Burshtyn D.N Long E.O Regulation through inhibitory receptors lessons from natural killer cells.Trends Cell Biol. 1997; 7: 473-479Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 41Renard V Cambiaggi A Vely F Blery M Olcese L Olivero S Bouchet M Vivier E Transduction of cytotoxic signals in natural killer cells a general model of fine tuning between activatory and inhibitory pathways in lymphocytes.Immunol. Rev. 1997; 155: 205-221Crossref PubMed Scopus (103) Google Scholar). Specifically, immunoreceptor tyrosine-based inhibitory motifs (ITIMs) are present on the intracellular portion of inhibitory Ly-49 receptors, KIRs, and the NKG2-A subunit of the CD94/NKG2A complex. Tyrosine phosphorylation of the ITIMs results in the recruitment of SH2 domain–containing phosphatases, including SHP-1. Recruited SHP-1 inhibits proximal protein tyrosine kinase activation, a requisite event for the initiation of NK cell–mediated cytotoxicity. Even though this review has focused on the inhibitory forms of the MHC-recognizing receptors, homologs have been identified in each case that have the potential to trigger activation. In each case, the activating homolog lacks any ITIM in its cytoplasmic domain, and, instead, has a charged residue in its transmembrane domain that enables it to specifically bind to an immunoreceptor tyrosine-based activation motif (ITAM)-containing subunit, DAP12 (21Lanier L.L Corliss B.C Wu J Leong C Phillips J.H Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells.Nature. 1998; 391 (a): 703-707Crossref PubMed Scopus (705) Google Scholar, 22Lanier L.L Corliss B Wu J Phillips J.H Association of DAP12 with activating CD94/NKG2C NK cell receptors.Immunity. 1998; 8 (b): 693-701Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar, 43Smith K.M Wu J Bakker A.B Phillips J.H Lanier L.L Ly-49D and Ly-49H associate with mouse DAP12 and form activating receptors.J. Immunol. 1998; 161: 7-10PubMed Google Scholar). Although cross-linking these receptors can induce NK cell–mediated cytotoxicity in vitro, their biologic role in vivo remains to be determined. While the observations regarding MHC-recognizing receptors on NK cells were emerging, separate analyses were focused on determining structural and functional differences between class Ia (classical) and class Ib (nonclassical) MHC molecules. Classical MHC class I structures include the association of a membrane-spanning, polymorphic 45 kDa heavy chain with an invariant 12 kDa light chain β2 microglobulin (Figure 1). Peptides of 8–10 amino acids in length are generated in the cytoplasm by proteolytic degradation, subsequently moving to the endoplasmic reticulum by a mechanism involving a specific transporter associated with antigen processing (TAP) and then binding to class Ia molecules (37Pamer E Cresswell P Mechanisms of MHC class I-restricted antigen presentation.Annu. Rev. Immunol. 1998; 16: 323-358Crossref PubMed Scopus (851) Google Scholar). The α1 and α2 domains of the class Ia heavy chain form the peptide-binding groove (4Bjorkman P.J Saper M.A Samraoui B Bennett W.S Strominger J.L Wiley D.C Structure of the human class I histocompatibility antigen, HLA A2.Nature. 1987; 329 (a): 506-512Crossref PubMed Scopus (2668) Google Scholar, 5Bjorkman P.J Saper M.A Samraoui B Bennett W.S Strominger J.L Wiley D.C The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens.Nature. 1987; 329 (b): 512-518Crossref PubMed Scopus (1785) Google Scholar), and the three-dimensional structure of this site places constraints on just two or three amino acid positions in the peptide (anchor positions). Other than at these anchor positions, there is marked flexibility in the peptide specificity of the binding site, allowing a diverse array of binding (28Madden D.R The three-dimensional structure of peptide-MHC complexes.Annu. Rev. Immunol. 1995; 13: 587-622Crossref PubMed Scopus (691) Google Scholar). In addition, the allelic polymorphisms of the heavy chain are centered around the peptide-binding groove, further increasing the diversity of peptides bound by class Ia molecules. These peptide-binding, ubiquitously-expressed class Ia molecules have the potential to be recognized by specialized receptors on T cells and NK cells. Nonclassical human HLA-E shares multiple features with class Ia molecules (Figure 1). The similar overall structure includes a heavy chain/β2 microglobulin/peptide complex. Sequence homology between HLA-E and HLA-A, -B, and -C varies between 50% and 90% (18Koller B.H Geraghty D.E Shimizu Y DeMars R Orr H.T HLA-E. A novel HLA class I gene expressed in resting T lymphocytes.J. Immunol. 1988; 141: 897-904PubMed Google Scholar). The ubiquitous tissue distribution of HLA-E matches that of MHC class Ia (47Wei X.H Orr H.T Differential expression of HLA-E, HLA-F, and HLA-G transcripts in human tissue.Hum. Immunol. 1990; 29: 131-142Crossref PubMed Scopus (189) Google Scholar, 24Lee N Llano M Carretero M Ishitani A Navarro F López-Botet M Geraghty D.E HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A.Proc. Natl. Acad. Sci. USA. 1998; 95 (b): 5199-5204Crossref PubMed Scopus (749) Google Scholar). However, there are notable differences between HLA-E and HLA-A, -B, and -C that suggest distinct biologic function. HLA-E has limited polymorphism (2 alleles identified) (15Geraghty D.E Stockschleader M Ishitani A Hansen J.A Polymorphism at the HLA-E locus predates most HLA-A and -B polymorphism.Hum. Immunol. 1992; 33: 174-184Crossref PubMed Scopus (97) Google Scholar, 16Grimsley C Ober C Population genetic studies of HLA-E. Evidence for selection.Hum. Immunol. 1997; 52: 33-40Crossref PubMed Scopus (103) Google Scholar), and there are unique amino acid substitutions within the peptide-binding groove at highly invariant positions that contribute to a restricted peptide-binding specificity (alanine at position 67, serine for threonine at position 143, and serine for tryptophan at position 147) (44Soloski M.J DeCloux A Aldrich C.J Forman J Structural and functional characteristics of the class IB molecule, Qa-1.Immunol. Rev. 1995; 147: 67-89Crossref PubMed Scopus (63) Google Scholar). The crystal structure of HLA-E reveals a constellation of requirements for hydrophobicity, size, configuration, and hydrogen bonding that leads to remarkably high peptide specificity (36O'Callaghan C.A Tormo J Willcox B.E Braud V.M Jakobsen B.K Stuart D.I McMichael A.J Bell J.I Jones E.Y Structural features impose tight peptide binding specificity in the nonclassical MHC molecule HLA-E.Mol. Cell. 1998; 1: 531-541Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). What provided an extraordinary twist in our understanding of HLA-E was the observation that the principal ligands bound to HLA-E are peptides derived from the leader sequences of HLA class Ia molecules (7Braud V Jones E.Y McMichael A The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9.Eur. J. Immunol. 1997; 27: 1164-1169Crossref PubMed Scopus (354) Google Scholar). Human class I leader sequences are remarkably conserved, with the only major variations occurring at P2 (methionine and threonine), P7 (leucine and valine), and P8 (leucine, isoleucine, and valine). Methionine at P2 is permissive, whereas threonine abrogates HLA-E binding (7Braud V Jones E.Y McMichael A The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9.Eur. J. Immunol. 1997; 27: 1164-1169Crossref PubMed Scopus (354) Google Scholar, 8Braud V.M Allan D.S.J Wilson D McMichael A.J TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide.Curr. Biol. 1998; 8 (a): 1-10Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 23Lee N Goodlett D.R Ishitani A Marquardt H Geraghty D.E HLA-E surface expression depends on binding of TAP-dependent peptides derived from certain HLA class I signal sequences.J. Immunol. 1998; 160 (a): 4951-4960PubMed Google Scholar). Since allelic forms of HLA-A and HLA-C, and some HLA-B, have methionine at P2, leader sequences from a broad range of HLA class Ia molecules are bound to HLA-E. In addition, the leader sequence from nonclassical HLA-G also binds well to HLA-E (7Braud V Jones E.Y McMichael A The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9.Eur. J. Immunol. 1997; 27: 1164-1169Crossref PubMed Scopus (354) Google Scholar). Importantly, significant cell surface expression of HLA-E depends on binding to leader sequence–derived peptides (8Braud V.M Allan D.S.J Wilson D McMichael A.J TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide.Curr. Biol. 1998; 8 (a): 1-10Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 23Lee N Goodlett D.R Ishitani A Marquardt H Geraghty D.E HLA-E surface expression depends on binding of TAP-dependent peptides derived from certain HLA class I signal sequences.J. Immunol. 1998; 160 (a): 4951-4960PubMed Google Scholar). Since intact TAP function is required for the peptide/HLA-E interaction and peptides from the leader sequence of HLA-E itself are not capable of binding, cell surface expression of HLA-E broadly reflects the integrity of the MHC class Ia–dependent antigen presentation pathway. In mice, the class Ib gene Qa-1 and its gene products share multiple features with HLA-E (44Soloski M.J DeCloux A Aldrich C.J Forman J Structural and functional characteristics of the class IB molecule, Qa-1.Immunol. Rev. 1995; 147: 67-89Crossref PubMed Scopus (63) Google Scholar). The gene has low allelic polymorphism, and Qa-1b molecules are ubiquitously expressed. Qa-1b has the same unique amino acid substitutions in the peptide-binding groove (positions 67, 143, and 147) that contribute to restricted binding specificity. Qa-1b cell surface expression requires TAP-dependent binding of peptides derived from the leader sequence of class Ia molecules (1Aldrich C.J DeCloux A Woods A.S Cotter R.J Soloski M.J Forman J Identification of a Tap-dependent leader peptide recognized by alloreactive T cells specific for a class Ib antigen.Cell. 1994; 79: 649-658Abstract Full Text PDF PubMed Scopus (242) Google Scholar, 12DeCloux A Woods A.S Cotter R.J Soloski M.J Forman J Dominance of a single peptide bound to the class IB molecule, Qa-1b.J. Immunol. 1997; 158: 2183-2191PubMed Google Scholar), and, in fact, Qa-1b will actually bind conserved class I leader peptides derived from multiple mammalian species (19Kurepa Z Hasemann C Forman J Qa-1b binds conserved class I leader peptides derived from several mammalian species.J. Exp. Med. 1998; in pressGoogle Scholar). In contrast, its own leader sequence (three amino acids shorter) will not bind to Qa-1b, allowing Qa-1b cell surface expression, like that of HLA-E, to broadly reflect whether the class Ia–dependent antigen presentation pathway is intact. Qa-1/peptide complexes can be recognized by TCR on T lymphocytes (46Vidovic D Roglic M McKune K Guerder S MacKay C Dembic Z Qa-1 restricted recognition of foreign antigen by a gamma delta T-cell hybridoma.Nature. 1989; 340: 646-650Crossref PubMed Scopus (191) Google Scholar, 1Aldrich C.J DeCloux A Woods A.S Cotter R.J Soloski M.J Forman J Identification of a Tap-dependent leader peptide recognized by alloreactive T cells specific for a class Ib antigen.Cell. 1994; 79: 649-658Abstract Full Text PDF PubMed Scopus (242) Google Scholar), but the precise role of this form of recognition remains unclear. As alluded to earlier in the text, results from the initial attempts to define the MHC specificity of the CD94/NKG2 complex were quite confounding. Most of the experimental approaches involved comparing the susceptibility of class Ia–deficient cell lines versus specific class Ia transfectants to NK cell–mediated cytotoxicity. The premise was that if an NK clone bearing inhibitory CD94/NKG2 could kill the class Ia–deficient cell line but was unable to kill a specific class Ia transfectant, this would suggest that the CD94/NKG2 recognized that particular MHC class Ia molecule. This assumption would be further supported if anti-CD94-specific antibody used to block a CD94/NKG2-MHC interaction reversed the resistant phenotype. Using this approach, results suggested that CD94/NKG2 could recognize most, but not all, allelic forms of HLA-A, -B, -C, and -G (38Pazmany L Mandelboim O Valés-Gómez M Davis D.M Reyburn H.T Strominger J.L Protection from natural killer cell-mediated lysis by HLA-G expression on target cells.Science. 1996; 274: 792-795Crossref PubMed Scopus (309) Google Scholar, 40Phillips J.H Chang C Mattson J Gumperz J.E Parham P Lanier L.L CD94 and a novel associated protein (94AP) form a NK cell receptor involved in the recognition of HLA-A, HLA-B, and HLA-C allotypes.Immunity. 1996; 5: 163-172Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 42Sivori S Vitale M Bottino C Marcenaro E Sanseverino L Parolini S Moretta L Moretta A CD94 functions as a natural killer cell inhibitory receptor for different HLA class I alleles identification of the inhibitory form of CD94 by the use of novel monoclonal antibodies.Eur. J. Immunol. 1996; 26: 2487-2492Crossref PubMed Scopus (121) Google Scholar). What was troubling was the absence of any common structural feature in the extracellular domains of the protective MHC that differentiated them from the nonprotective MHC. In addition, predictions that certain antibodies specific for class I MHC would reverse the resistant phenotype by blocking a CD94/NKG2-MHC interaction were not borne out. However, several groups grasped a subtlety to the experimental model that had not been fully appreciated before (6Borrego F Ulbrecht M Weiss E.H Coligan J.E Brooks A.G Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis.J. Exp. Med. 1998; 187: 813-818Crossref PubMed Scopus (555) Google Scholar, 9Braud V.M Allan D.S O'Callaghan C.A Söderström K D'Andrea A Ogg G.S Lazetic S Young N.T Bell J.I Phillips J.H et al.HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.Nature. 1998; 391 (b): 795-799Crossref PubMed Scopus (1596) Google Scholar, 24Lee N Llano M Carretero M Ishitani A Navarro F López-Botet M Geraghty D.E HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A.Proc. Natl. Acad. Sci. USA. 1998; 95 (b): 5199-5204Crossref PubMed Scopus (749) Google Scholar). First, they noted the reports indicating that significant HLA-E cell surface expression requires binding to class Ia–derived leader sequence peptides. Therefore, class Ia–deficient cell lines would not only lack class Ia, but would also have minimal cell surface HLA-E expression. As a corollary, class Ia transfectants would express not only the transfected gene product, but would also up-regulate HLA-E expression if the transfected gene coded for a leader sequence permissive for HLA-E binding. In fact, the specific class Ia transfectants that appeared to be resistant to killing by the CD94/NKG2+ NK clones were the class Ia genes whose leader sequence–derived peptides had been shown to bind HLA-E. These observations are all consistent with the notion that CD94/NKG2 recognizes HLA-E rather than class Ia molecules. Three groups provided formal evidence suggesting that CD94/NKG2 recognizes, perhaps exclusively, HLA-E. In order to demonstrate a direct CD94/NKG2-HLA-E interaction, Braud and colleagues utilized tetramers in which HLA-E and β2 microglobulin were folded with an MHC leader sequence peptide (9Braud V.M Allan D.S O'Callaghan C.A Söderström K D'Andrea A Ogg G.S Lazetic S Young N.T Bell J.I Phillips J.H et al.HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.Nature. 1998; 391 (b): 795-799Crossref PubMed Scopus (1596) Google Scholar). These tetramers selectively bound to normal cells bearing CD94 (NK cells and a subset of T cells) and to cells transfected with either CD94/NKG2-A/B (inhibitory receptor) or CD94/NKG2-C (activating receptor). In addition, two separate strategies were used to up-regulate HLA-E expression on class Ia–deficient lines. One approach used synthetic peptides corresponding to the leader sequences of permissive class Ia molecules (6Borrego F Ulbrecht M Weiss E.H Coligan J.E Brooks A.G Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis.J. Exp. Med. 1998; 187: 813-818Crossref PubMed Scopus (555) Google Scholar). The other involved transfecting class Ia-deficient cells with genes encoding chimeric proteins that would enhance HLE expression (e.g., permissive HLA-A2-derived signal sequence and the extracellular portion of HLA-E) (9Braud V.M Allan D.S O'Callaghan C.A Söderström K D'Andrea A Ogg G.S Lazetic S Young N.T Bell J.I Phillips J.H et al.HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.Nature. 1998; 391 (b): 795-799Crossref PubMed Scopus (1596) Google Scholar, 24Lee N Llano M Carretero M Ishitani A Navarro F López-Botet M Geraghty D.E HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A.Proc. Natl. Acad. Sci. USA. 1998; 95 (b): 5199-5204Crossref PubMed Scopus (749) Google Scholar). In each case, up-regulation of HLA-E expression conferred resistance against CD94/NKG2A-bearing NK cells. Neutralizing antibody specific for either HLA-E or CD94/NKG2 restored lysis. Taken together, these data clearly suggest that HLA-E complexed with specific peptides from class Ia–derived leader sequences acts as a major ligand for inhibitory CD94/NKG2-A (Figure 1). The role of HLA-E recognition on NK cells bearing the activating CD94/NKG2-C is less clear. The HLA-E tetramers do bind CD94/NKG2-C-bearing cells (9Braud V.M Allan D.S O'Callaghan C.A Söderström K D'Andrea A Ogg G.S Lazetic S Young N.T Bell J.I Phillips J.H et al.HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.Nature. 1998; 391 (b): 795-799Crossref PubMed Scopus (1596) Google Scholar). Furthermore, cells expressing HLA-E bound to leader sequences derived from the class Ib molecule HLA-G can induce killing by CD94/NKG2-C-bearing NK cells (26Llano M Lee N Navarro F Garcia P Albar J.P Geraghty D.E López-Botet M HLA-E-bound peptides influence recognition by inhibitory and triggering CD94/NKG2 receptors preferential response to an HLA-G-derived nonamer.Eur. J. Immunol. 1998; in pressGoogle Scholar). Interestingly, this induction of killing is markedly less effective for HLA-E bound to leader sequences from class Ia molecules. Therefore, how different NKG2 family members influence MHC-specificity, the role of different leader sequence peptides in NK cell recognition, and the physiologic in vivo consequences of HLA-E recognition by activating CD94/NKG2 receptors all remain to be determined. HLA-E recognition by CD94/NKG2 could potentially serve many functions. NK cells bearing these receptors could provide potent defense against tumor cells with reduced class Ia expression or against viruses that down-regulate class Ia expression by transcriptional mechanisms, altering heavy chain stability or interfering with TAP function. The resultant reduction in the availability of class Ia–derived peptide should reduce cell surface HLA-E expression, resulting in potential increased susceptibility to NK cells bearing inhibitory CD94-NKG2-A receptors. Further work will be needed to determine if viruses have evolved an escape mechanism whereby their induced decrease in class Ia expression is coupled to the coding for peptides that could bind to HLA-E and therefore restore HLA-E expression. If so, one potential reason for having both class Ia–recognizing inhibitory receptors (e.g., human KIRs and murine Ly-49) and class Ib–recognizing inhibitory CD94-NKG2-A would be to provide ongoing defense against viruses of this kind. In addition, since peptides from HLA-G leader sequences also bind HLA-E, CD94/NKG2 expression by uterine decidual NK cells could affect materno–fetal interactions. HLA-G is the predominant class I molecule expressed on fetally derived placental trophoblast cells, with extravillous cytotrophoblasts expressing high levels of HLA-G upon their entry into the maternal decidua. If HLA-G biosynthesis results in the expression of HLA-E, maternally derived cytotoxic lymphocytes bearing inhibitory CD94/NKG2 could be prevented from interacting with the semiallogeneic trophoblasts. Alternatively, lymphocytes bearing activating CD94/NKG2 could block trophoblast infiltration into sites where these cells would reside. The above described functions could provide the kind of selective advantage that would account for the remarkably high degree of evolutionary conservation for the expression of HLA-E homologs. The major focus in this review has been on the role of CD94/NKG2 on NK cellular activation. However, several recent observations raise the possibility that activation-induced expression of CD94/NKG2 on a subset of CTLs may also critically influence CTL function (32Mingari M.C Moretta A Moretta L Regulation of KIR expression in human T cells a safety mechanism that may impair protective T-cell responses.Immunol. 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Additional analyses indicated that the majority of this T cell subset is CD8+ and has a phenotype consistent with memory T cells (high levels of CD18, CD29, CD57, and CD45RO and an absence of CD28) (30Mingari M.C Schiavetti F Ponte M Vitale C Maggi E Romagnani S Demarest J Pantaleo G Fauci A.S Moretta L Human CD8+ T lymphocyte subsets that express HLA class I-specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations.Proc. Natl. Acad. Sci. USA. 1996; 93: 12433-12438Crossref PubMed Scopus (222) Google Scholar, 31Mingari M.C Ponte M Cantoni C Vitale C Schiavetti F Bertone S Bellomo R Cappai A.T Biassoni R HLA-class I-specific inhibitory receptors in human cytolytic T lymphocytes molecular characterization, distribution in lymphoid tissues and co-expression by individual T cells.Int. Immunol. 1997; 9: 485-491Crossref PubMed Scopus (67) Google Scholar). Furthermore, cross-linking KIRs or CD94/NKG2 strongly inhibits CTL-mediated cytotoxicity (14Ferrini S Cambiaggi A Meazza R Sforzini S Marciano S Mingari M.C Moretta L T cell clones expressing the natural killer cell-related p58 receptor molecule display heterogeneity in phenotypic properties and p58 function.Eur. J. Immunol. 1994; 24: 2294-2298Crossref PubMed Scopus (133) Google Scholar, 29Mingari M.C Vitale C Cambiaggi A Schiavetti F Melioli G Ferrini S Poggi A Cytolytic T lymphocytes displaying natural killer (NK)-like activity expression of NK-related functional receptors for HLA class I molecules (p58 and CD94) and inhibitory effect on the TCR-mediated target cell lysis or lymphokine production.Int. Immunol. 1995; 7: 697-703Crossref PubMed Scopus (208) Google Scholar, 39Phillips J.H Gumperz J.E Parham P Lanier L.L Superantigen-dependent, cell-mediated cytotoxicity inhibited by MHC class I receptors on T lymphocytes.Science. 1995; 268: 403-405Crossref PubMed Scopus (298) Google Scholar). These observations raise the possibility that inhibitory MHC-recognizing receptors could contribute to the down-regulation of a CTL response. Recent analyses suggest that IL-15 induces the expression of CD94/NKG2-A on a sizeable fraction of CTLs responding to alloantigens or superantigens (33Mingari M.C Ponte M Bertone S Schiavetti F Vitale C Bellomo R Moretta A Moretta L HLA class I-specific inhibitory receptors in human T lymphocytes interleukin 15-induced expression of CD94/NKG2A in superantigen- or alloantigen-activated CD8+ T cells.Proc. Natl. Acad. Sci. USA. 1998; 95 (b): 1172-1177Crossref PubMed Scopus (206) Google Scholar). The CD94/NKG2-expressing CTLs appear to be inhibited in their cytolytic capability, since CD94-specific antibody used to block potential CD94/NKG2-MHC interactions enhances allospecific cytolytic activity. These observations raise the possibility that depending on the cytokine milieu in a localized inflammatory reaction, inhibitory CD94/NKG2-A receptors may be induced on CTLs, with the subsequent down-regulation of their cytolytic activity. Since the leader sequences from many HLA class I molecules can bind to HLA-E and, therefore, induce its expression, many CD94/NKG2-bearing CTLs, irrespective of the MHC-specificity of their TCR, could undergo this suppressed function. Importantly, it remains to be determined what other cytokines affect CD94/NKG2 expression and whether certain pathologic forms of immunosuppression (e.g., tumor-bearing individuals) or specific autoimmune diseases involve the inappropriate presence or absence of CD94/NKG2 on CTL, respectively. The striking experimental observations summarized in this review reveal a novel mechanism whereby a receptor that binds to a highly specific ligand can be utilized to broadly assess complex and heterogeneous cellular functions. Specifically, CD94/NKG2-mediated recognition of HLA-E enables cytotoxic lymphocytes to determine whether potential targets have defects in any one of multiple possible steps in the antigen/MHC class I presentation pathway. Other receptors have evolved that are capable of directly binding specific subgroups of MHC class Ia molecules (e.g., human Ig domain–containing KIRs and rodent Ly-49). However, since functional MHC-recognizing homologs for KIRs and Ly-49 have not been identified broadly across species, these receptors may represent somewhat specialized adaptations. In contrast, the striking conservation across species of CD94/NKG2 and of MHC class Ib molecules bearing signal sequence peptides derived from MHC class Ia molecules indicates that their interaction subserves critical, conserved biologic roles. Exploring their implications to antitumor immunity, antiviral immunity, autoimmunity, materno–fetal interactions, and lymphocyte homeostasis should provide new insights as to their critical regulatory functions. I want to thank Lewis Lanier, Miguel López-Botet, Lorenzo Moretta, and James Forman for sharing with me prepublication manuscripts. I also want to thank Larry Pease for his helpful discussions and Bryce Binstadt and Kathy Brumbaugh for their critical reviews of the manuscript.
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