CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms

Nat Immunol. 2010 Feb;11(2):129-35. doi: 10.1038/ni.1835. Epub 2009 Dec 27.

Abstract

The inhibitory immunoregulatory receptor CTLA-4 is critical in maintaining self-tolerance, but the mechanisms of its actions have remained controversial. Here we examined the antigen specificity of tissue-infiltrating CD4(+) T cells in Ctla4(-/-) mice. After adoptive transfer, T cells isolated from tissues of Ctla4(-/-) mice showed T cell antigen receptor (TCR)-dependent accumulation in the tissues from which they were derived, which suggested reactivity to tissue-specific antigens. We identified the pancreas-specific enzyme PDIA2 as an autoantigen in Ctla4(-/-) mice. CTLA-4 expressed either on PDIA2-specific effector cells or on regulatory T cells was sufficient to control tissue destruction mediated by PDIA2-specific T cells. Our results demonstrate that both cell-intrinsic and non-cell-autonomous actions of CTLA-4 operate to maintain T cell tolerance to a self antigen.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, CD / immunology*
  • Autoantigens / immunology*
  • CTLA-4 Antigen
  • Flow Cytometry
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Transgenic
  • Protein Disulfide-Isomerases / immunology
  • Receptors, Antigen, T-Cell / immunology
  • Self Tolerance / immunology*
  • T-Lymphocyte Subsets / immunology*

Substances

  • Antigens, CD
  • Autoantigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Receptors, Antigen, T-Cell
  • PDIA2 protein, human
  • Protein Disulfide-Isomerases