T cell receptor interactions with human leukocyte antigen govern indirect peptide selectivity for the cancer testis antigen MAGE-A4

Abstract

T cell-mediated immunity is governed primarily by T cell receptor (TCR) recognition of peptide-human leukocyte antigen (pHLA) complexes and is essential for immunosurveillance and disease control. This interaction is generally stabilized by interactions between the HLA surface and TCR germline-encoded complementarity-determining region (CDR) loops 1 and 2, whereas peptide selectivity is guided by direct interactions with the TCR CDR3 loops. Here, we solved the structure of a newly identified TCR in complex with a clinically relevant peptide derived from the cancer testis antigen melanoma antigen-A4 (MAGE-A4). The TCR bound pHLA in a position shifted toward the peptide's N terminus. This enabled the TCR to achieve peptide selectivity via an indirect mechanism, whereby the TCR sensed the first residue of the peptide through HLA residue Trp-167, which acted as a tunable gateway. Amino acid substitutions at peptide position 1 predicted to alter the HLA Trp-167 side-chain conformation abrogated TCR binding, indicating that this indirect binding mechanism is essential for peptide recognition. These findings extend our understanding of the molecular rules that underpin antigen recognition by TCRs and have important implications for the development of TCR-based therapies. T cell-mediated immunity is governed primarily by T cell receptor (TCR) recognition of peptide-human leukocyte antigen (pHLA) complexes and is essential for immunosurveillance and disease control. This interaction is generally stabilized by interactions between the HLA surface and TCR germline-encoded complementarity-determining region (CDR) loops 1 and 2, whereas peptide selectivity is guided by direct interactions with the TCR CDR3 loops. Here, we solved the structure of a newly identified TCR in complex with a clinically relevant peptide derived from the cancer testis antigen melanoma antigen-A4 (MAGE-A4). The TCR bound pHLA in a position shifted toward the peptide's N terminus. This enabled the TCR to achieve peptide selectivity via an indirect mechanism, whereby the TCR sensed the first residue of the peptide through HLA residue Trp-167, which acted as a tunable gateway. Amino acid substitutions at peptide position 1 predicted to alter the HLA Trp-167 side-chain conformation abrogated TCR binding, indicating that this indirect binding mechanism is essential for peptide recognition. These findings extend our understanding of the molecular rules that underpin antigen recognition by TCRs and have important implications for the development of TCR-based therapies. T cell–mediated immunity is essential during pathogen and cancer surveillance and plays a key role in autoimmunity and transplant rejection (1Coppieters K.T. 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Gras S. Miles J.J. S.J. McCluskey J. T cell antigen receptor recognition of Rev. Immunol. PubMed Scopus Google the TCR a of with the the and N of the the TCR the and of the and the TCR and loops the peptide and and TCR-pHLA of of in a this the TCR to many TCR-pHLA complex J. Gras S. Miles J.J. S.J. McCluskey J. T cell antigen receptor recognition of Rev. Immunol. PubMed Scopus Google with of the HLA and in to the in the peptide and and its abrogated its to direct with the HLA from the TCR with HLA and Trp-167, and peptide focused toward with the of with the TCR and These interactions in a TCR-pHLA surface of and of the with the which the for TCR-pHLA complexes J. Gras S. Miles J.J. S.J. McCluskey J. T cell antigen receptor recognition of Rev. Immunol. PubMed Scopus Google Scholar). of the V. W. A. M. structure of in complex with a peptide by the Biol. 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Full Text Full Text PDF PubMed Scopus Google and that in peptide can have that alter the and TCR of peptide V. Bulek A. Fuller A. A. M. Rizkallah Dolton G. Sewell Cole molecular T-cell receptor (TCR) of a human melanoma Biol. Chem. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). a of studies have that flexibility in the peptide and the HLA can guide epitope to T cells M. M. G. M. M. S. is a peptide affinity of J. Immunol. 2012; 42 PubMed Scopus Google Scholar, Baker B.M. and peptide-dependent motions in implications and biophysical Immunol. 2017; 8 PubMed Scopus Google Scholar, Piepenbrink K.H. B.E. Cole D.K. Sewell A.K. Baker B.M. T cell receptor by of peptide-MHC molecular 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, B.E. K. E. Baker B.M. of complex protein molecular flexibility and the implications for Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. C. F. Baker B.M. in peptide-dependent of flexibility.Front. 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TCR binding to peptide-MHC stabilizes a flexible recognition interface.Immunity. 1999; 10 (10204491): 357-36510.1016/S1074-7613(00)80035-7Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar). TCR to the and of and with an as D.K. Yuan F. Rizkallah P.J. Miles J.J. Gostick E. Price D.A. Gao G.F. Jakobsen B.K. Sewell A.K. Germ line-governed recognition of a cancer epitope by an immunodominant human T-cell receptor.J. Biol. Chem. 2009; 284 (19605354): 27281-2728910.1074/jbc.M109.022509Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). The expressed with surface a and in the of and the as D.K. Yuan F. Rizkallah P.J. Miles J.J. Gostick E. Price D.A. Gao G.F. Jakobsen B.K. Sewell A.K. Germ line-governed recognition of a cancer epitope by an immunodominant human T-cell receptor.J. Biol. Chem. 2009; 284 (19605354): 27281-2728910.1074/jbc.M109.022509Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). TCRs and a TCR D.K. Yuan F. Rizkallah P.J. Miles J.J. Gostick E. Price D.A. Gao G.F. Jakobsen B.K. Sewell A.K. Germ line-governed recognition of a cancer epitope by an immunodominant human T-cell receptor.J. Biol. Chem. 2009; 284 (19605354): 27281-2728910.1074/jbc.M109.022509Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). binding analyses a with a as D.K. Rizkallah P.J. M. Vuidepot A. M. Gao F. Bell J.I. Jakobsen B.K. Gao G.F. and structure of an affinity human CD8 PubMed Scopus Google Scholar). as a on cell and analyses at of pHLA to the The TCR at from and the of the interaction at 10 The binding and the a of protein of in a in a at in a for the TCR-pHLA complex in the 1 to of protein of a to of from an in a of the a of and at K. at at the at the at TCR-pHLA and and through the P.A. K. and 2012; PubMed Scopus Google and in the and to Molecular to and and and as in A.J. Adams P.D. PubMed Scopus Google Scholar). the as TCR-pHLA of and in E.J. of by the Biol. PubMed Scopus Google Scholar) as TCR-pHLA in P. 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