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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • Cross Reactions / immunology
  • Fibroblasts
  • HEK293 Cells
  • HIV Infections / immunology*
  • HIV-1 / immunology*
  • HLA-D Antigens / immunology*
  • Healthy Volunteers
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Jurkat Cells
  • Leukocytes, Mononuclear
  • Lymphocyte Activation
  • Mice
  • Primary Cell Culture
  • Receptors, Antigen, T-Cell / immunology
  • Viral Load / immunology
  • Virus Replication / immunology

Substances

  • HLA-D Antigens
  • Receptors, Antigen, T-Cell