Absence of co-stimulation and not the intensity of TCR signaling is critical for the induction of T cell unresponsiveness in vivo

Eur J Immunol. 1999 Jul;29(7):2156-66. doi: 10.1002/(SICI)1521-4141(199907)29:07<2156::AID-IMMU2156>3.0.CO;2-P.

Abstract

Understanding the mechanisms of T cell activation versus induction of unresponsiveness is of critical importance for the rational modulation of immune responses. Efficient T cell activation is critical for vaccination purposes, while the inhibition of T cell responses is potentially important for the ablation of autoimmune diseases. Modulation of co-stimulation and changing TCR-mediated signaling using altered peptide ligands (APL) have been shown to result in clonal T cell unresponsiveness. This study compares for the first time the efficiency of the two approaches for the induction of CD8+ T cell unresponsiveness in vivo for naive and memory T cells using TCR-transgenic mice. The results demonstrate that inhibition of CD28-mediated co-stimulation in the presence of a strong TCR-mediated signal most efficiently induces T cell unresponsiveness. In contrast, APL that are capable of weak TCR triggering fail to interfere with T cell responsiveness in vivo and are ignored by T cells. Thus, short-term blockage of CD28 during antigenic stimulation rather than the use of APL is the most promising way to actively down-modulate responsiveness of naive CD8+ T cells at least in the particular TCR-transgenic mouse model analyzed in this study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CD28 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • Down-Regulation
  • Immune Tolerance*
  • Immunologic Memory
  • In Vitro Techniques
  • Ligands
  • Lymphocyte Activation*
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Transgenic
  • Oligopeptides / chemistry
  • Oligopeptides / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • Viral Proteins / chemistry
  • Viral Proteins / immunology

Substances

  • CD28 Antigens
  • Ligands
  • Oligopeptides
  • Receptors, Antigen, T-Cell
  • Viral Proteins