Abstract

CD8+ CTL responses directed toward the HLA-B*51:01–restricted HIV-RT128–135 epitope TAFTIPSI (TI8) are associated with long-term nonprogression to AIDS. Clonotypic analysis of responses to B51-TI8 revealed a public clonotype using TRAV17/TRBV7-3 TCR genes in six out of seven HLA-B*51:01+ patients. Structural analysis of a TRAV17/TRBV7-3 TCR in complex with HLA–B51-TI8, to our knowledge the first human TCR complexed with an 8-mer peptide, explained this bias, as the unique combination of residues encoded by these genes was central to the interaction. The relatively featureless peptide-MHC (pMHC) was mainly recognized by the TCR CDR1 and CDR2 loops in an MHC-centric manner. A highly conserved residue Arg97 in the CDR3α loop played a major role in recognition of peptide and MHC to form a stabilizing ball-and-socket interaction with the MHC and peptide, contributing to the selection of the public TCR clonotype. Surface plasmon resonance equilibrium binding analysis showed the low affinity of this public TCR is in accordance with the only other 8-mer interaction studied to date (murine 2C TCR–H-2Kb-dEV8). Like pMHC class II complexes, 8-mer peptides do not protrude out the MHC class I binding groove like those of longer peptides. The accumulated evidence suggests that weak affinity might be a common characteristic of TCR binding to featureless pMHC landscapes.

Highlights

  • We focused on seven HLA-B*51:01+ Japanese individuals chronically infected with HIV-1 because HLA-B*51:01–restricted TI8-specific CTLs were induced by stimulating PBMCs from only these individuals with TI8 peptides

  • The TCRb-chain was encoded by a combination of the TRBV7-3, TRBJ2-2, and TRBD2 genes, with CDR3 sequence CASSLTGGELFF, in patients KI-021 and KI-051, whereas the TRBJ1-4 and TRBD1 or D2 were used in conjunction with TRBV7-3 in patients KI-112, KI-127, and KI-250 to produce the CDR3 sequence CASSLTGGKLFF

  • Previous studies with HLA-B*27 and HLA-B*57 have identified residue identical public TCR responses [defined as residue-identical receptors found across different individuals who share a common MHC [22, 31]] against HIV [32,33,34,35]

Read more

Summary

Introduction

Clonotypic analysis of responses to B51-TI8 revealed a public clonotype using TRAV17/ TRBV7-3 TCR genes in six out of seven HLA-B*51:01+ patients. We identified a public CTL clone (3B) expressing a TCR encoded by TRAV17/ TRBV7-3 TCR genes, specific for B51-TI8.

Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call