Stimulation of CD25(+)CD4(+) Regulatory T Cells Through GITR Breaks Immunological Self-Tolerance

Nat Immunol. 2002 Feb;3(2):135-42. doi: 10.1038/ni759. Epub 2002 Jan 22.

Abstract

CD25(+)CD4(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18)--a member of the tumor necrosis factor-nerve growth factor (TNF-NGF) receptor gene superfamily--is predominantly expressed on CD25(+)CD4(+) T cells and on CD25(+)CD4(+)CD8(-) thymocytes in normal naïve mice. We found that stimulation of GITR abrogated CD25(+)CD4(+) T cell-mediated suppression. In addition, removal of GITR-expressing T cells or administration of a monoclonal antibody to GITR produced organ-specific autoimmune disease in otherwise normal mice. Thus, GITR plays a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / etiology
  • CD4 Antigens / isolation & purification
  • CD4-Positive T-Lymphocytes / immunology*
  • Dimerization
  • Glucocorticoid-Induced TNFR-Related Protein
  • Glycoproteins / antagonists & inhibitors
  • Glycoproteins / immunology
  • Glycoproteins / metabolism
  • Immune Tolerance / immunology*
  • Lymph Nodes / immunology
  • Mice
  • Mice, Inbred BALB C
  • Rats
  • Rats, Wistar
  • Receptors, Interleukin-2 / isolation & purification
  • Receptors, Nerve Growth Factor / antagonists & inhibitors
  • Receptors, Nerve Growth Factor / immunology
  • Receptors, Nerve Growth Factor / metabolism*
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Signal Transduction
  • Spleen / immunology
  • T-Lymphocyte Subsets / immunology*

Substances

  • CD4 Antigens
  • Glucocorticoid-Induced TNFR-Related Protein
  • Glycoproteins
  • Receptors, Interleukin-2
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf18 protein, mouse