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

Journal Article · · Nature Communications
 [1];  [2];  [3];  [4];  [5];  [6];  [6];  [4];  [7];  [3];  [6];  [8];  [9];  [6];  [8];  [6];  [6];  [6];  [10];  [11] more »;  [12] « less
  1. Univ. of Science and Technology of China, Hefei (China); Dana-Farber Cancer Institute, Boston, MA (United States); Harvard Medical School, Boston, MA (United States); Ragon Inst. of Mass General, MIT, and Harvard, Cambridge, MA (United States)
  2. Ragon Inst. of Mass General, MIT, and Harvard, Cambridge, MA (United States); Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA (United States); Howard Hughes Medical Inst., Chevy Chase, MD (United States)
  3. Ragon Inst. of Mass General, MIT, and Harvard, Cambridge, MA (United States); Howard Hughes Medical Inst., Chevy Chase, MD (United States)
  4. Dana-Farber Cancer Institute, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
  5. Ragon Inst. of Mass General, MIT, and Harvard, Cambridge, MA (United States); Dana-Farber Cancer Institute, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
  6. Ragon Inst. of Mass General, MIT, and Harvard, Cambridge, MA (United States)
  7. Argonne National Laboratory (ANL), Argonne, IL (United States)
  8. IBM, Yorktown Heights, NY (United States). Thomas J. Watson Research Center
  9. Ragon Inst. of Mass General, MIT, and Harvard, Cambridge, MA (United States); Massachusetts General Hospital, Boston, MA (United States)
  10. IBM, Yorktown Heights, NY (United States). Thomas J. Watson Research Center; Columbia Univ., New York, NY (United States); Zhejiang Univ., Hangzhou (China)
  11. Ragon Inst. of Mass General, MIT, and Harvard, Cambridge, MA (United States); Howard Hughes Medical Inst., Chevy Chase, MD (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
  12. Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Institute, Boston, MA (United States)
+ Show Author Affiliations
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.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
Bill and Melinda Gates Foundation; IBM Corporation; National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
2404852
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

60 APPLIED LIFE SCIENCES
HIV infections
cellular immunity
cytotoxic T cells
immunological memory
x-ray crystallography