Highly divergent T-cell receptor binding modes underlie specific recognition of a bulged viral peptide bound to a human leukocyte antigen class I molecule

Liu, Yu Chih, Miles, John J., Neller, Michelle A., Gostick, Emma, Price, David A., Purcell, Anthony W., McCluskey, James, Burrows, Scott R., Rossjohn, Jamie, and Gras, Stephanie (2013) Highly divergent T-cell receptor binding modes underlie specific recognition of a bulged viral peptide bound to a human leukocyte antigen class I molecule. Journal of Biological Chemistry, 288 (22). pp. 15442-15454.

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Abstract

Human leukocyte antigen (HLA)-I molecules can present long peptides, yet the mechanisms by which T-cell receptors (TCRs) recognize featured pHLA-I landscapes are unclear. We compared the binding modes of three distinct human TCRs, CA5, SB27, and SB47, complexed with a "super-bulged" viral peptide (LPEPLPQGQLTAY) restricted by HLA-B*35:08. The CA5 and SB27 TCRs engaged HLA-B*35:08^LPEP similarly, straddling the central region of the peptide but making limited contacts with HLA-B*35:08. Remarkably, the CA5 TCR did not contact the α1-helix of HLA-B*35:08. Differences in the CDR3β loop between the CA5 and SB27 TCRs caused altered fine specificities. Surprisingly, the SB47 TCR engaged HLA-B*35:08^LPEP using a completely distinct binding mechanism, namely "bypassing" the bulged peptide and making extensive contacts with the extreme N-terminal end of HLA-B*35:08. This docking footprint included HLA-I residues not observed previously as TCR contact sites. The three TCRs exhibited differing patterns of alloreactivity toward closely related or distinct HLA-I allotypes. Thus, the human T-cell repertoire comprises a range of TCRs that can interact with "bulged" pHLA-I epitopes using unpredictable strategies, including the adoption of atypical footprints on the MHC-I.

Item ID: 45108
Item Type: Article (Research - C1)
ISSN: 1083-351X
Keywords: major histocompatibility complex (MHC); structural biology; T-cell receptor; viral immunology; X-ray crystallography
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Free via Creative Commons: CC-BY license.

Funders: Australian Research Council (ARC), National Health and Medical Research Council of Australia (NHMRC), Wellcome Trust (WT)
Projects and Grants: ARC Grant DP110102078, NHMRC APP1009326
Date Deposited: 16 Aug 2016 02:06
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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