Nonstimulatory peptide-MHC enhances human T-cell antigen-specific responses by amplifying proximal TCR signaling

Nat Commun. 2018 Jul 13;9(1):2716. doi: 10.1038/s41467-018-05288-0.

Abstract

Foreign antigens are presented by antigen-presenting cells in the presence of abundant endogenous peptides that are nonstimulatory to the T cell. In mouse T cells, endogenous, nonstimulatory peptides have been shown to enhance responses to specific peptide antigens, a phenomenon termed coagonism. However, whether coagonism also occurs in human T cells is unclear, and the molecular mechanism of coagonism is still under debate since CD4 and CD8 coagonism requires different interactions. Here we show that the nonstimulatory, HIV-derived peptide GAG enhances a specific human cytotoxic T lymphocyte response to HBV-derived epitopes presented by HLA-A*02:01. Coagonism in human T cells requires the CD8 coreceptor, but not T-cell receptor (TCR) binding to the nonstimulatory peptide-MHC. Coagonists enhance the phosphorylation and recruitment of several molecules involved in the TCR-proximal signaling pathway, suggesting that coagonists promote T-cell responses to antigenic pMHC by amplifying TCR-proximal signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigen Presentation
  • Antigen-Presenting Cells / cytology
  • Antigen-Presenting Cells / immunology
  • Antigens / chemistry
  • Antigens / genetics
  • Antigens / immunology*
  • CHO Cells
  • Cricetulus
  • Epitopes / chemistry
  • Epitopes / genetics
  • Epitopes / immunology*
  • Gene Expression
  • HLA-A2 Antigen / genetics
  • HLA-A2 Antigen / immunology*
  • Humans
  • Immunological Synapses / immunology
  • Immunological Synapses / ultrastructure
  • Lymphocyte Activation
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / immunology*
  • Plasmids / chemistry
  • Plasmids / immunology
  • Receptors, Antigen, T-Cell / chemistry
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Signal Transduction / immunology*
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transfection
  • gag Gene Products, Human Immunodeficiency Virus / genetics
  • gag Gene Products, Human Immunodeficiency Virus / immunology

Substances

  • Antigens
  • Epitopes
  • HLA-A2 Antigen
  • Peptides
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • gag Gene Products, Human Immunodeficiency Virus