Molecular basis of differential HLA class I-restricted T cell recognition of a highly networked HIV peptide

Xiaolong Li (), Nishant Kumar Singh, David R. Collins, Robert Ng, Angela Zhang, Pedro A. Lamothe-Molina, Peter Shahinian, Shutong Xu, Kemin Tan, Alicja Piechocka-Trocha, Jonathan M. Urbach, Jeffrey K. Weber, Gaurav D. Gaiha, Overbeck Christian Takou Mbah, Tien Huynh, Sophia Cheever, James Chen, Michael Birnbaum, Ruhong Zhou, Bruce D. Walker () and Jia-huai Wang ()
Additional contact information
Xiaolong Li: University of Science and Technology of China
Nishant Kumar Singh: Ragon Institute of MGH, MIT and Harvard
David R. Collins: Ragon Institute of MGH, MIT and Harvard
Robert Ng: Dana-Farber Cancer Institute, Harvard Medical School
Angela Zhang: Ragon Institute of MGH, MIT and Harvard
Pedro A. Lamothe-Molina: Ragon Institute of MGH, MIT and Harvard
Peter Shahinian: Ragon Institute of MGH, MIT and Harvard
Shutong Xu: Dana-Farber Cancer Institute, Harvard Medical School
Kemin Tan: Argonne National Laboratory
Alicja Piechocka-Trocha: Ragon Institute of MGH, MIT and Harvard
Jonathan M. Urbach: Ragon Institute of MGH, MIT and Harvard
Jeffrey K. Weber: Computational Biology Center
Gaurav D. Gaiha: Ragon Institute of MGH, MIT and Harvard
Overbeck Christian Takou Mbah: Ragon Institute of MGH, MIT and Harvard
Tien Huynh: Computational Biology Center
Sophia Cheever: Ragon Institute of MGH, MIT and Harvard
James Chen: Ragon Institute of MGH, MIT and Harvard
Michael Birnbaum: Ragon Institute of MGH, MIT and Harvard
Ruhong Zhou: Computational Biology Center
Bruce D. Walker: Ragon Institute of MGH, MIT and Harvard
Jia-huai Wang: Dana-Farber Cancer Institute, Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Cytotoxic-T-lymphocyte (CTL) mediated control of HIV-1 is enhanced by targeting highly networked epitopes in complex with human-leukocyte-antigen-class-I (HLA-I). However, the extent to which the presenting HLA allele contributes to this process is unknown. Here we examine the CTL response to QW9, a highly networked epitope presented by the disease-protective HLA-B57 and disease-neutral HLA-B53. Despite robust targeting of QW9 in persons expressing either allele, T cell receptor (TCR) cross-recognition of the naturally occurring variant QW9_S3T is consistently reduced when presented by HLA-B53 but not by HLA-B57. Crystal structures show substantial conformational changes from QW9-HLA to QW9_S3T-HLA by both alleles. The TCR-QW9-B53 ternary complex structure manifests how the QW9-B53 can elicit effective CTLs and suggests sterically hindered cross-recognition by QW9_S3T-B53. We observe populations of cross-reactive TCRs for B57, but not B53 and also find greater peptide-HLA stability for B57 in comparison to B53. These data demonstrate differential impacts of HLAs on TCR cross-recognition and antigen presentation of a naturally arising variant, with important implications for vaccine design.

Date: 2023
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DOI: 10.1038/s41467-023-38573-8

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