CD4+ T cell-mediated HLA class II cross-restriction in HIV controllers

  • Sci Immunol. 2018 Jun 8;3(24):eaat0687. doi: 10.1126/sciimmunol.aat0687.
Moran Galperin  1 ,  Carine Farenc  2 ,  Madhura Mukhopadhyay  1 ,  Dhilshan Jayasinghe  2 ,  Amandine Decroos  1 ,  Daniela Benati  1 ,  Li Lynn Tan  2 ,  Lisa Ciacchi  2 ,  Hugh H Reid  2  3 ,  Jamie Rossjohn  2  3  4 ,  Lisa A Chakrabarti  1  5 ,  Stephanie Gras  2  3
Affiliations
  • 1. Pasteur Institute, Viral Pathogenesis Unit, Paris, France.
  • 2. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
  • 3. ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
  • 4. Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
  • 5. INSERM, U1108, Paris, France.
PMID: 29884618 DOI: 10.1126/sciimmunol.aat0687
Abstract

Rare individuals, termed HIV controllers, spontaneously control HIV Infection by mounting efficient T cell responses against the virus. Protective CD4+ T cell responses from HIV controllers involve high-affinity public T cell receptors (TCRs) recognizing an immunodominant capsid epitope (Gag293) presented by a remarkably broad array of human leukocyte antigen (HLA) class II molecules. Here, we determine the structures of a prototypical public TCR bound to HLA-DR1, HLA-DR11, and HLA-DR15 molecules presenting the Gag293 epitope. TCR recognition was driven by contacts with the Gag293 epitope, a feature that underpinned the extensive HLA cross-restriction. These high-affinity TCRs promoted mature immunological synapse formation and cytotoxic capacity in both CD4+ and CD8+ T cells. The public TCRs suppressed HIV replication in multiple genetic backgrounds ex vivo, emphasizing the functional advantage conferred by broad HLA class II cross-restriction.