Germ Line-governed Recognition of a Cancer Epitope by an Immunodominant Human T-cell Receptor

CD8+ T-cells specific for MART-1-(26–35), a dominant melanoma epitope restricted by human leukocyte antigen (HLA)-A*0201, are exceptionally common in the naive T-cell repertoire. Remarkably, the TRAV12-2 gene is used to encode the T-cell receptor α (TCRα) chain in >87% of these T-cells. Here, the molecular basis for this genetic bias is revealed from the structural and thermodynamic properties of an archetypal TRAV12-2-encoded TCR complexed to the clinically relevant heteroclitic peptide, ELAGIGILTV, bound to HLA-A*0201 (A2-ELA). Unusually, the TRAV12-2 germ line-encoded regions of the TCR dominate the major atomic contacts with the peptide at the TCR/A2-ELA interface. This “innate” pattern of antigen recognition probably explains the unique characteristics and extraordinary frequencies of CD8+ T-cell responses to this epitope. CD8+ T-cells specific for MART-1-(26–35), a dominant melanoma epitope restricted by human leukocyte antigen (HLA)-A*0201, are exceptionally common in the naive T-cell repertoire. Remarkably, the TRAV12-2 gene is used to encode the T-cell receptor α (TCRα) chain in >87% of these T-cells. Here, the molecular basis for this genetic bias is revealed from the structural and thermodynamic properties of an archetypal TRAV12-2-encoded TCR complexed to the clinically relevant heteroclitic peptide, ELAGIGILTV, bound to HLA-A*0201 (A2-ELA). Unusually, the TRAV12-2 germ line-encoded regions of the TCR dominate the major atomic contacts with the peptide at the TCR/A2-ELA interface. This “innate” pattern of antigen recognition probably explains the unique characteristics and extraordinary frequencies of CD8+ T-cell responses to this epitope. Malignant melanoma is responsible for 75% of all skin cancer-related deaths worldwide, and the global incidence is rising. The MART-1 (1Kawakami Y. Eliyahu S. Sakaguchi K. Robbins P.F. Rivoltini L. Yannelli J.R. Appella E. Rosenberg S.A. J. Exp. Med. 1994; 180: 347-352Crossref PubMed Scopus (770) Google Scholar) protein, also known as Melan-A (2Romero P. Valmori D. Pittet M.J. Zippelius A. Rimoldi D. Lévy F. Dutoit V. Ayyoub M. Rubio-Godoy V. Michielin O. Guillaume P. Batard P. Luescher I.F. Lejeune F. Liénard D. Rufer N. Dietrich P.Y. Speiser D.E. Cerottini J.C. Immunol. Rev. 2002; 188: 81-96Crossref PubMed Scopus (133) Google Scholar), is expressed by virtually all fresh melanoma tumor specimens and elicits natural CD8+ T-cell responses (3Voelter V. Rufer N. Reynard S. Greub G. Brookes R. Guillaume P. Grosjean F. Fagerberg T. Michelin O. Rowland-Jones S. Pinilla C. Leyvraz S. Romero P. Appay V. Int. Immunol. 2008; 20: 1087-1096Crossref PubMed Scopus (12) Google Scholar, 4Pittet M.J. Valmori D. Dunbar P.R. Speiser D.E. Liénard D. Lejeune F. Fleischhauer K. Cerundolo V. Cerottini J.C. Romero P. J. Exp. Med. 1999; 190: 705-715Crossref PubMed Scopus (418) Google Scholar) that can lead to spontaneous disease regression (reviewed in Ref. 5Chodorowski Z. Anand J.S. Wiœniewski M. Madaliñski M. Wierzba K. Wiœniewski J. Przegl. Lek. 2007; 64: 380-382PubMed Google Scholar). Consequently, CD8+ T-cell responses directed against the MART-1 protein have been investigated extensively (reviewed in Refs. 2Romero P. Valmori D. Pittet M.J. Zippelius A. Rimoldi D. Lévy F. Dutoit V. Ayyoub M. Rubio-Godoy V. Michielin O. Guillaume P. Batard P. Luescher I.F. Lejeune F. Liénard D. Rufer N. Dietrich P.Y. Speiser D.E. Cerottini J.C. Immunol. Rev. 2002; 188: 81-96Crossref PubMed Scopus (133) Google Scholar, 6Pittet M.J. Zippelius A. Valmori D. Speiser D.E. Cerottini J.C. Romero P. Trends Immunol. 2002; 23: 325-328Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, and 7Kawakami Y. Rosenberg S.A. Int. Rev. Immunol. 1997; 14: 173-192Crossref PubMed Scopus (94) Google Scholar), and heteroclitic forms of the dominant MART-1-(26–35) peptide epitope (8Speiser D.E. Liénard D. Pittet M.J. Batard P. Rimoldi D. Guillaume P. Cerottini J.C. Romero P. Eur. J. Immunol. 2002; 32: 731-741Crossref PubMed Scopus (92) Google Scholar, 9Valmori D. Fonteneau J.F. Lizana C.M. Gervois N. Liénard D. Rimoldi D. Jongeneel V. Jotereau F. Cerottini J.C. Romero P. J. Immunol. 1998; 160: 1750-1758PubMed Google Scholar), which is restricted by human leukocyte antigen (HLA)-A*0201, are currently being used in a number of clinical trials (10Bins A. Mallo H. Sein J. van den Bogaard C. Nooijen W. Vyth-Dreese F. Nuijen B. de Gast G.C. Haanen J.B. J. Immunother. 2007; 30: 234-239Crossref PubMed Scopus (21) Google Scholar, 11Chen Q. Jackson H. Shackleton M. Parente P. Hopkins W. Sturrock S. MacGregor D. Maraskovsky E. Tai T.Y. Dimopoulos N. Masterman K.A. Luke T. Davis I.D. Chen W. Cebon J. Cancer Immun. 2005; 5: 5PubMed Google Scholar, 12Meidenbauer N. Marienhagen J. Laumer M. Vogl S. Heymann J. Andreesen R. Mackensen A. J. Immunol. 2003; 170: 2161-2169Crossref PubMed Scopus (142) Google Scholar). In recent developments, adoptive T-cell therapy directed against the MART-1 protein has been used to mediate cancer regression in ∼50% of late stage melanoma patients (13Morgan R.A. Dudley M.E. Wunderlich J.R. Hughes M.S. Yang J.C. Sherry R.M. Royal R.E. Topalian S.L. Kammula U.S. Restifo N.P. Zheng Z. Nahvi A. de Vries C.R. Rogers-Freezer L.J. Mavroukakis S.A. Rosenberg S.A. Science. 2006; 314: 126-129Crossref PubMed Scopus (2065) Google Scholar). However, these approaches have not proved to be universally effective, and there remains considerable scope for improvement. In order to design more effective immune-based therapies against the MART-1 protein, it is essential to understand the precise molecular rules that govern the interaction between T-cell receptors (TCRs) 6The abbreviations used are: TCRT-cell receptorMHCmajor histocompatibility complexpMHCpeptide major histocompatibility complexCDRcomplementarity-determining regionHLAhuman leukocyte antigenvdWvan der WaalsA2-ELAELAGIGILTV bound to HLA-A*0201pMHCIpMHC class Iβ2mβ2-microglobulin. 6The abbreviations used are: TCRT-cell receptorMHCmajor histocompatibility complexpMHCpeptide major histocompatibility complexCDRcomplementarity-determining regionHLAhuman leukocyte antigenvdWvan der WaalsA2-ELAELAGIGILTV bound to HLA-A*0201pMHCIpMHC class Iβ2mβ2-microglobulin. and the HLA-A*0201·MART-1-(26–35) complex. Previous structural studies of human TCR/peptide major histocompatibility complex (pMHC) interactions (14Rudolph M.G. Stanfield R.L. Wilson I.A. Annu. Rev. Immunol. 2006; 24: 419-466Crossref PubMed Scopus (892) Google Scholar, 15Tynan F.E. Reid H.H. Kjer-Nielsen L. Miles J.J. Wilce M.C. Kostenko L. Borg N.A. Williamson N.A. Beddoe T. Purcell A.W. Burrows S.R. McCluskey J. Rossjohn J. Nat. Immunol. 2007; 8: 268-276Crossref PubMed Scopus (175) Google Scholar, 16Armstrong K.M. Piepenbrink K.H. Baker B.M. Biochem. J. 2008; 415: 183-196Crossref PubMed Scopus (93) Google Scholar) indicate that specific regions of the TCR have different roles during antigen engagement; thus, the germ line-encoded complementarity-determining region 1 and 2 (CDR1 and -2) loops contact mainly the conserved helical region of the MHC surface, and the more variable somatically rearranged CDR3 loops contact mainly the antigenic peptide. Dissecting the nature of these contacts, which have been shown to be highly variable for individual TCR/pMHC interactions (17Borg N.A. Ely L.K. Beddoe T. Macdonald W.A. Reid H.H. Clements C.S. Purcell A.W. Kjer-Nielsen L. Miles J.J. Burrows S.R. McCluskey J. Rossjohn J. Nat. Immunol. 2005; 6: 171-180Crossref PubMed Scopus (151) Google Scholar, 18Feng D. Bond C.J. Ely L.K. Maynard J. Garcia K.C. Nat. Immunol. 2007; 8: 975-983Crossref PubMed Scopus (173) Google Scholar, 19Tynan F.E. Borg N.A. Miles J.J. Beddoe T. El-Hassen D. Silins S.L. van Zuylen W.J. Purcell A.W. Kjer-Nielsen L. McCluskey J. Burrows S.R. Rossjohn J. J. Biol. Chem. 2005; 280: 23900-23909Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar), is an important step toward understanding the principles of antigen recognition and for the development of improved T-cell vaccines (20Borbulevych O.Y. Baxter T.K. Yu Z. Restifo N.P. Baker B.M. J. Immunol. 2005; 174: 4812-4820Crossref PubMed Scopus (90) Google Scholar). However, the current data base of human TCR·pMHC complexes reported in the literature is limited (∼16), compared with >100 antibody-antigen structures. This has made it difficult to ascertain whether there are conserved binding modes for TCR/pMHC interactions dictated by a number of specific contacts or whether there are potentially unlimited numbers of TCR docking orientations dependent on the nature of individual recognition events. Furthermore, there are no examples to date of human TCR·pMHC class I structures in which the bound peptide is a decamer; this represents a substantial deficiency in our current knowledge, given the preponderance with which decamer peptides are processed, presented, and recognized. The low number of TCR·pMHC complex structures solved to date reflects technical difficulties inherent in the production of soluble TCR and pMHC molecules that retain stability and challenges related to the crystallization of complexes with relatively low binding affinities (KD M. E. J. Immunol. 2007; PubMed Scopus Google Scholar, A. Y. A. T. R. A. M.E. R.E. Nat. Med. 2008; 14: PubMed Scopus Google Scholar). In specific for in the of TCR/pMHC affinities M. E. J. Immunol. 2007; PubMed Scopus Google Scholar). This to the of is by the that human complex has been G. G. L. G. Dunbar P.R. R.M. M. P. C. A. van der G. Cerundolo V. J. Exp. Med. 2005; PubMed Scopus Google Scholar). T-cell receptor major histocompatibility complex peptide major histocompatibility complex complementarity-determining region human leukocyte antigen van der bound to HLA-A*0201 pMHC class I T-cell receptor major histocompatibility complex peptide major histocompatibility complex complementarity-determining region human leukocyte antigen van der bound to HLA-A*0201 pMHC class I In this expressed a soluble TCR specific for ELAGIGILTV, the common MART-1-(26–35) heteroclitic peptide, complexed to HLA-A*0201 (A2-ELA). HLA-A*0201 is the common in the human P. M. D. K.M. M. D. PubMed Scopus Google Scholar). The and loops of this TCR are by the TRAV12-2 and the TRAV12-2 gene is expressed in the of CD8+ T-cell specific for HLA-A*0201·MART-1-(26–35) L. N. Jotereau F. V. Gervois N. T. P. M. Eur. J. Immunol. 2002; 32: PubMed Scopus Google Scholar, P.Y. Dutoit V. Pittet M.J. L. Zippelius A. V. P.R. Michielin O. Guillaume P. T. Jotereau F. Romero P. Cerottini J.C. M. Valmori D. J. Immunol. 2003; 170: PubMed Scopus Google Scholar). the of the dominant TRAV12-2 gene and the molecular characteristics that govern CD8+ T-cell recognition of the HLA-A*0201·MART-1-(26–35) a and structural of TCR binding to The data a molecular basis for TCR gene in the CD8+ T-cell to HLA-A*0201·MART-1-(26–35) and indicate that pMHC can be to binding modes CD8+ T-cell as B. van den E. L. J. A. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). from an with 1 peptide and for The CD8+ T-cell from these in to with the peptide, specific and the production of and tumor not The TCR from the CD8+ T-cell CD8+ T-cell in the and shown to an The HLA-A*0201 α chain and by and by a used to the soluble and for the α and P. PubMed Scopus Google Scholar, M. E. M. P. 2003; PubMed Scopus Google Scholar). The soluble HLA-A*0201 α chain and chain with a and also and used to the HLA-A*0201 The HLA-A*0201 α and the of the P. PubMed Scopus Google Scholar). used to the α and and the HLA-A*0201 α and in the of to as P. PubMed Scopus Google Scholar). a of α chain at for with and to 2 and of at for with a of α chain with of and of the peptide at for This to 2 and at for against the of the 2 The in for the by a and and or crystallization a by pMHC as J.R. Davis van der 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). a with a as reported M. Immunol. 2008; PubMed Scopus Google Scholar). and of pMHC to which to the The pMHC at a to on the with the of pMHC bound to the surface, this the of and to on the of to the of TCR the and in for and the relevant at the at a of the thermodynamic this at the and and The binding a The thermodynamic the The complex as reported F. T. T. E. R. J. A. M. F. Biol. 2007; PubMed Scopus Google Scholar). data to with the at an The to of of The at in an with the on Scholar), and the data and with and the Biol. 1994; PubMed Scopus Google Scholar). The solved with molecular Biol. 2005; PubMed Scopus Google Scholar). to complexes solved or a be with a with as the HLA-A*0201 α chain from the chain from the chain from and the chain from The peptide not at this it a of the The with P. K. Biol. PubMed Scopus Google Scholar), and the with Biol. 1997; PubMed Scopus Google Scholar). The for peptide, and of in order to the for with The Scholar). and and are shown in and in are for the in are for the of of in the from in are in are for the in are in a the structural basis for dominant TRAV12-2 gene in CD8+ T-cell specific for solved the atomic of in complex with in with the of of the complex and the to that the between the molecules and The of in the and regions of the and with the data The and the protein to the of 2 and The of the chain with no that The docking with as in Ref. M.G. Stanfield R.L. Wilson I.A. Annu. Rev. Immunol. 2006; 24: 419-466Crossref PubMed Scopus (892) Google Scholar), with the chain the and the chain the of The docking in this complex the for human TCR·pMHC with the complex P. PubMed Scopus Google Scholar) and the G. G. L. G. Dunbar P.R. R.M. M. P. C. A. van der G. Cerundolo V. J. Exp. Med. 2005; PubMed Scopus Google Scholar) complex the The TCR toward the of the MHC peptide binding as in the and complexes 1998; 8: Full Text Full Text PDF PubMed Scopus Google Scholar, Baker B.M. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), and the of the peptide and The of the interaction the for human TCR/pMHC interaction reported to This the that contacts with the pMHC compared with which that T-cell recognition of antigen can with a number of specific contacts the peptide is a the of the peptide of the to TCR binding the for complexes that in the peptide binding The of the and has been shown to for different human TCR·pMHC the being for the complex Nat. Immunol. 2003; PubMed Scopus Google Scholar) the the interaction relatively The the as a with a of between the MHC and the TCR However, the to the TCR and the peptide a and more directed forms contacts, interactions and van der with the conserved MHC α of HLA-A*0201 that the of the peptide binding contacts are by the which is the of the peptide and a to the a of interactions between the chain and the MHC and the no in the antigen contacts between the MHC and the TCR and as in number of or interactions that are in the of complex structures solved to date (14Rudolph M.G. Stanfield R.L. Wilson I.A. Annu. Rev. Immunol. 2006; 24: 419-466Crossref PubMed Scopus (892) Google Scholar), also between and the MHC interactions between the TCR and the MHC and between the TCR and and the MHC not contact MHC or which the contacts (14Rudolph M.G. Stanfield R.L. Wilson I.A. Annu. Rev. Immunol. 2006; 24: 419-466Crossref PubMed Scopus (892) Google van der van der in a The of has been solved P. Michielin O. Cerottini J.C. Luescher Romero P. M. J. Immunol. PubMed Scopus Google Scholar). the peptide is a it a to peptides with a between and In the of the peptide, the is not a more by an of the peptide chain toward the of the HLA-A*0201 binding of the and the structures that the peptide are at virtually This peptide in the of a number of for specific TCR these and with the the of the peptide docking with the TCR is with a of between the peptides in and are in the of and which different in the these are and not in peptide to of the peptide TCR contacts of the peptide 2 and compared with for the L. Clements C.S. Purcell A.W. J.C. Burrows S.R. McCluskey J. Rossjohn J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) and the for Nat. Immunol. 2003; PubMed Scopus Google Scholar) Unusually, the has a in the peptide, interaction between TCR and the peptide at substantial number of contacts at the are between in the by the TRAV12-2 and the antigenic peptide The a of contacts to and and is to have a in peptide recognition 2 and In this TCR binding the in a with that of a CDR3 with to peptide The of the in of the of HLA-A*0201 and the bound peptide the of the TRAV12-2 gene in CD8+ T-cell responses specific for MART-1-(26–35) P.Y. Dutoit V. Pittet M.J. L. Zippelius A. V. P.R. Michielin O. Guillaume P. T. Jotereau F. Romero P. Cerottini J.C. M. Valmori D. J. Immunol. 2003; 170: PubMed Scopus Google Scholar). Furthermore, the TRAV12-2 which the and loops of is also expressed by the which is specific for the peptide bound to HLA-A*0201 P. PubMed Scopus Google Scholar). The and loops of the TCR an antigen binding virtually to that in the with contacts between and MHC and between and peptide 1 and and for and for In all TCR·pMHC the and which are not by the TRAV12-2 unique contacts with pMHC complexes compared with the this to the that the TRAV12-2 gene have a binding to antigen restricted by HLA-A*0201 to germ or recognition of on the MHC and in the bound peptide. Consequently, the and relatively in the TCR and the in the of the chain in complexes that the TCR and to in an the binding of these is by the α The chain a peptide binding with the peptide contacts made by the In the and interactions between and of the TCR and and of the peptide. However, all of the which the of the binding are between the and the of the peptide and the of the a of between TCR and and peptide contacts are the chain of an toward the MHC surface, it an for TCR the contacts between the and the peptide to the binding stability of the complex. have shown that to with a and compared with TCR/pMHC interactions (KD to M. E. J. Immunol. 2007; PubMed Scopus Google Scholar). the thermodynamic properties of this the binding of to at and a and The of the interaction from at to at The data as binding regression to the to the in order to and the interaction by a of which is the for TCR/pMHC interactions The interaction is with a of This is to be mainly from the of molecules complex the TCR to contact the pMHC and the and interactions in the this is the of a TCR/pMHC interaction that is with a of 2 This that there is a in the number of and during complex and the of the to the binding of to Furthermore, this the of the interaction the of lead to the low and the of the complex there is a in the which in a In the of the a relatively compared with TCR·pMHC This the that the of for the complex is the reported to date for TCR·pMHC of the in a Here, the of an archetypal TRAV12-2-encoded TCR from a CD8+ T-cell specific for MART-1-(26–35) in complex with is currently the heteroclitic peptide in the literature and is to a number of clinical trials (10Bins A. Mallo H. Sein J. van den Bogaard C. Nooijen W. Vyth-Dreese F. Nuijen B. de Gast G.C. Haanen J.B. J. Immunother. 2007; 30: 234-239Crossref PubMed Scopus (21) Google Scholar, 11Chen Q. Jackson H. Shackleton M. Parente P. Hopkins W. Sturrock S. MacGregor D. Maraskovsky E. Tai T.Y. Dimopoulos N. Masterman K.A. Luke T. Davis I.D. Chen W. Cebon J. Cancer Immun. 2005; 5: 5PubMed Google Scholar, 12Meidenbauer N. Marienhagen J. Laumer M. Vogl S. Heymann J. Andreesen R. Mackensen A. J. Immunol. 2003; 170: 2161-2169Crossref PubMed Scopus (142) Google Scholar). the peptide is a heteroclitic of the MART-1-(26–35) peptide structural that the of to at the peptide 2 not the peptide P. Michielin O. Cerottini J.C. Luescher Romero P. M. J. Immunol. PubMed Scopus Google Scholar, O.Y. Baxter T.K. Restifo N.P. Baker B.M. J. Biol. 2007; PubMed Scopus Google Scholar). an understanding of the molecular basis for T-cell recognition of this antigen the of current melanoma Previous have shown that CD8+ T-cells the HLA-A*0201·MART-1-(26–35) antigen with TCR gene P.Y. Dutoit V. Pittet M.J. L. Zippelius A. V. P.R. Michielin O. Guillaume P. T. Jotereau F. Romero P. Cerottini J.C. M. Valmori D. J. Immunol. 2003; 170: PubMed Scopus Google Scholar, D. Dutoit V. Liénard D. Lejeune F. Speiser D. Rimoldi D. Cerundolo V. Dietrich P.Y. Cerottini J.C. Romero P. J. Immunol. PubMed Scopus Google Scholar). these class bias the and class bias the McCluskey J. Rossjohn J. Nat. Rev. Immunol. 2006; 6: PubMed Scopus Google can also be in and in the of and P.Y. Dutoit V. Pittet M.J. L. Zippelius A. V. P.R. Michielin O. Guillaume P. T. Jotereau F. Romero P. Cerottini J.C. M. Valmori D. J. Immunol. 2003; 170: PubMed Scopus Google Scholar, D. Dutoit V. Liénard D. Lejeune F. Speiser D. Rimoldi D. Cerundolo V. Dietrich P.Y. Cerottini J.C. Romero P. J. Immunol. PubMed Scopus Google Scholar). T-cells specific for the HLA-A*0201 MART-1-(26–35) antigen bias in gene recent revealed of CD8+ T-cell on the HLA-A*0201 MART-1-(26–35) expressed a TCR of the TRAV12-2 P.Y. Dutoit V. Pittet M.J. L. Zippelius A. V. P.R. Michielin O. Guillaume P. T. Jotereau F. Romero P. Cerottini J.C. M. Valmori D. J. Immunol. 2003; 170: PubMed Scopus Google Scholar). This bias the TRAV12-2 gene is expressed on the of of T. T. S. Y. T. T. R. J. Immunol. 1997; PubMed Scopus Google Scholar), the of TRAV12-2 in these CD8+ T-cell responses that this gene is during The TRAV12-2-encoded regions of the TCR a dominant at the peptide and MHC interface. The to the TCR to the MHC the to peptide recognition and interactions to and In the a with that of the CDR3 in TCR·pMHC given the of the peptide and the binding between the and bound peptide. is to that by the TRAV12-2 gene of of the interactions with more of the TCR regions in this Furthermore, the are it the TRAV12-2 is in of encode at and of encode at the TRAV12-2 gene In the highly of and probably not be given that encode a at This probably in the of interactions at the pMHC interface. In of this no specific for the HLA-A*0201·MART-1-(26–35) complex have been that the or the P.Y. Dutoit V. Pittet M.J. L. Zippelius A. V. P.R. Michielin O. Guillaume P. T. Jotereau F. Romero P. Cerottini J.C. M. Valmori D. J. Immunol. 2003; 170: PubMed Scopus Google Scholar). the dominant of this TCR probably represents an during responses against the HLA-A*0201·MART-1-(26–35) antigen that be by of of the complex that to the dominant of the TRAV12-2-encoded in CD8+ T-cell responses specific for contacts the chain of the of peptide contacts are chain This is from the more of chain chain peptide interactions in TCR·pMHC structures and that be to peptide to peptide the somatically rearranged chain to contact the peptide, the germ line-encoded chain to contact the peptide. This of binding between the and loops in the complex have for antigen thus, in the of the be binding to as as the of the is in the of the T-cell recognition of to of the TRAV12-2 gene is also used by the which is specific for the this is the structural in which an gene is between specific for a tumor antigen and a antigen In of these the TRAV12-2 loops are the of This the loops of TCR to more contacts with the antigenic peptide compared with the In the to the of TCR·pMHC with the mainly to MHC contacts and the mainly to peptide Furthermore, the that and the TCR are by unique chain and the in virtually and orientations the molecules in the and the that the chain by the TRAV12-2 gene has a dominant during docking compared with the This to the that and the TCR are binding is by common contacts between the chain and the MHC D. Bond C.J. Ely L.K. Maynard J. Garcia K.C. Nat. Immunol. 2007; 8: 975-983Crossref PubMed Scopus (173) Google Scholar). the unique of the peptides in the and the binding by the by the germ TRAV12-2 gene in the complex and the complex is virtually thus, contacts between the and the MHC between the and peptide 1 and and for and for are in complex structures and the of for the HLA-A*0201·MART-1-(26–35) antigen is not the highly variable somatically rearranged CDR3 as for TCR·pMHC also the germ which to peptide considerable contacts between the TCR loops and the antigenic peptide have been in TCR·pMHC complexes F.E. Burrows S.R. Clements C.S. Borg N.A. Miles J.J. Beddoe T. J.C. Wilce M.C. Silins S.L. Burrows Kjer-Nielsen L. Kostenko L. Purcell A.W. McCluskey J. Rossjohn J. Nat. Immunol. 2005; 6: PubMed Scopus Google Scholar), this is the of specific antigen recognition germ line-encoded receptor loops by and T-cells. In this of a human TCR in complex with a decamer peptide bound to our of TCR/pMHC the interaction is the TCR interaction K.M. Baker B.M. J. 2008; PubMed Scopus Google Scholar). the complex has the of TCR·pMHC an that is by the relatively this that the of for is in interactions with the which to peptide binding and is to that of CDR3 loops during pMHC The of the germ line-encoded regions in this TCR during pMHC binding an important for the TRAV12-2 gene in antigen that the TRAV12-2 gene CD8+ T-cells to and to the HLA-A*0201·MART-1-(26–35) antigen a recognition probably the TCR that has been in CD8+ T-cell specific for HLA-A*0201·MART-1-(26–35) and reported in a of human (reviewed in Refs. McCluskey J. Rossjohn J. Nat. Rev. Immunol. 2006; 6: PubMed Scopus Google and J.J. Silins S.L. Burrows S.R. Med. Chem. 2006; PubMed Scopus Google Scholar). the at the for of the for and for with for with molecular