CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor

Proc Natl Acad Sci U S A. 2021 Jul 20;118(29):e2019639118. doi: 10.1073/pnas.2019639118.

Abstract

CD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used two intrinsically controlled systems to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR.

Keywords: CD8 coreceptor; T cell activation; pMHCI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens / chemistry
  • Antigens / immunology
  • CD8 Antigens / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • Cross Reactions
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Kinetics
  • Ligands
  • Lymphocyte Activation
  • Models, Immunological
  • Mutation
  • Peptides / agonists*
  • Peptides / immunology*
  • Receptors, Antigen, T-Cell / immunology*

Substances

  • Antigens
  • CD8 Antigens
  • Histocompatibility Antigens Class I
  • Ligands
  • Peptides
  • Receptors, Antigen, T-Cell