Delayed expansion of a restricted T cell repertoire by low-density TCR ligands

Int Immunol. 2005 Jul;17(7):931-41. doi: 10.1093/intimm/dxh273. Epub 2005 Jun 21.

Abstract

The role of TCR ligand density (i.e. the number of antigen-MHC complexes) in modulating the diversity of a T cell response selected from a pool of naive precursors remains largely undefined. By measuring early-activation markers up-regulation and proliferation following stimulation with staphylococcal enterotoxin A (SEA), we demonstrate that decreasing the ligand dose below an optimal concentration leads to the delayed activation of a restricted set of TCRVbeta-bearing T cells, with the specific, non-stochastic exclusion of some TCRVbeta+ T cells from the activated pool. Our results suggest that the failure of these TCRVbeta-bearing T cells to reach the activation threshold at sub-optimal ligand concentration is due to the inefficiency of TCR engagement, as measured by TCR internalization, and does not correlate with the relative precursor frequency in the non-immune repertoire. Moreover, even at SEA concentrations that lead to the simultaneous proliferation of all SEA-reactive T cells, we observe marked differences in the ability to secrete cytokines among the different responsive TCRVbeta-bearing T cells. Altogether, our results indicate that the development of a T cell response to a scarce display of ligand significantly narrows TCR repertoire diversity by mechanisms that involve focusing of the repertoire on the expansion of those T cells with the highest avidity of TCR engagement.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antigen Presentation / drug effects*
  • Antigen Presentation / immunology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Immunologic
  • Enterotoxins / pharmacology*
  • Gene Rearrangement, T-Lymphocyte / drug effects*
  • Gene Rearrangement, T-Lymphocyte / immunology
  • Humans
  • Interferon Inducers / pharmacology*
  • Ligands
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Activation / immunology
  • Receptors, Antigen, T-Cell, alpha-beta
  • T-Lymphocytes / immunology*

Substances

  • Enterotoxins
  • Interferon Inducers
  • Ligands
  • Receptors, Antigen, T-Cell, alpha-beta
  • enterotoxin A, Staphylococcal