TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis

Nat Med. 2006 Sep;12(9):1088-92. doi: 10.1038/nm1449. Epub 2006 Jul 20.

Abstract

TRAF6 has a key role in the regulation of innate immune responses by mediating signals from both TNF receptor and interleukin-1 receptor/Toll-like receptor superfamilies. Here we show that T cell-specific deletion of TRAF6 unexpectedly results in multiorgan inflammatory disease. TRAF6-deficient T cells exhibit hyperactivation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway compared with wild-type T cells and, as a result, become resistant to suppression by CD4+ CD25+ regulatory T cells. These data identify a previously unrecognized role for TRAF6 in the maintenance of peripheral tolerance, and suggest the presence of a T cell-intrinsic control mechanism to render responder T cells susceptible to tolerizing signals.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4 Antigens / physiology
  • Homeostasis / immunology*
  • Immune Tolerance / physiology*
  • Inflammation / immunology*
  • Interleukin-2 Receptor alpha Subunit / physiology
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • T-Lymphocytes / physiology*
  • T-Lymphocytes, Regulatory / physiology
  • TNF Receptor-Associated Factor 6 / deficiency
  • TNF Receptor-Associated Factor 6 / physiology*

Substances

  • CD4 Antigens
  • Interleukin-2 Receptor alpha Subunit
  • TNF Receptor-Associated Factor 6
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt