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; Jia-Huai Wang

doi:10.1038/s41467-023-38573-8

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

Nat Commun. 2023 May 22;14(1):2929. doi: 10.1038/s41467-023-38573-8.

Authors

Xiaolong Li^{1

2

3}, Nishant Kumar Singh^{4

5

6}, David R Collins^{4

6}, Robert Ng⁷, Angela Zhang^{4

7}, Pedro A Lamothe-Molina⁴, Peter Shahinian⁴, Shutong Xu⁷, Kemin Tan⁸, Alicja Piechocka-Trocha^{4

6}, Jonathan M Urbach⁴, Jeffrey K Weber⁹, Gaurav D Gaiha^{4

10}, Overbeck Christian Takou Mbah⁴, Tien Huynh⁹, Sophia Cheever⁴, James Chen⁴, Michael Birnbaum^{4

5}, Ruhong Zhou^{9

11

12}, Bruce D Walker^{13

14

15}, Jia-Huai Wang^{16

17

18}

Affiliations

¹ School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China. xiaolong@crystal.harvard.edu.
² Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA. xiaolong@crystal.harvard.edu.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA. xiaolong@crystal.harvard.edu.
⁴ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA.
⁵ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, 02142, USA.
⁶ Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
⁸ Structural Biology Center, X-ray Science Division, Advanced Photon Source, Argonne National Laboratory, Lemont, IL, 60439, USA.
⁹ IBM Thomas J. Watson Research Center, Computational Biology Center, Yorktown Heights, NY, 10598, USA.
¹⁰ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, 02114, USA.
¹¹ Department of Chemistry, Columbia University, New York, NY, 10025, USA.
¹² Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
¹³ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139, USA. bwalker@mgh.harvard.edu.
¹⁴ Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA. bwalker@mgh.harvard.edu.
¹⁵ Institute for Medical Engineering and Science and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. bwalker@mgh.harvard.edu.
¹⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA. jwang@crystal.harvard.edu.
¹⁷ Department of Pediatrics, Harvard Medical School, Boston, MA, 02215, USA. jwang@crystal.harvard.edu.
¹⁸ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02215, USA. jwang@crystal.harvard.edu.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Epitopes, T-Lymphocyte
HIV Infections*
HLA-B Antigens / genetics
Humans
Peptides
Receptors, Antigen, T-Cell
T-Lymphocytes, Cytotoxic

Substances

HLA-B Antigens
Peptides
Epitopes, T-Lymphocyte
Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding