TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis.
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.
King
Carolyn G
CG
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania 19104, USA.
Kobayashi
Takashi
T
Cejas
Pedro J
PJ
Kim
Taesoo
T
Yoon
Kwiyeom
K
Kim
Gregory K
GK
Chiffoleau
Elise
E
Hickman
Somia P
SP
Walsh
Patrick T
PT
Turka
Laurence A
LA
Choi
Yongwon
Y
D000818:Animals; D015704:CD4 Antigens / Q000502:physiology; D006706:Homeostasis / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D007249:Inflammation / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000502:physiology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000502:physiology*
D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D048029:TNF Receptor-Associated Factor 6; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt