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, Y., Miles, John James, Neller, M., Gostick, E., Price, David ORCID: https://orcid.org/0000-0001-9416-2737, Purcell, A., McCluskey, J., Burrows, S., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 and Gras, S. 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. 10.1074/jbc.M112.447185

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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 CA5and SB27 TCRs engaged HLA-B*35:08LPEP 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 Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General) R Medicine > RZ Other systems of medicine
Uncontrolled Keywords:	Binding mechanisms; Binding modes; Contact sites; Human leukocyte antigen; Human T Cells; Specific recognition; T-cell receptors; Viral peptides;CD8-Positive T-Lymphocytes; Complementarity Determining Regions; Herpesvirus 4, Human; HLA-B35 Antigen; Peptides; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, Antigen, T-Cell; Viral Proteins
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Date of First Compliant Deposit:	8 September 2017
Last Modified:	12 Jun 2023 19:37
URI:	https://orca.cardiff.ac.uk/id/eprint/76031

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