Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a.
Forkhead (Fox) transcription factors play key roles in immunoregulation. Members of the Foxo subfamily have been implicated in the regulation of the cell cycle and/or apoptosis, but their specific immunological contexts remain largely undefined. We demonstrate here that Foxo3a, the predominant Foxo member expressed in peripheral lymphoid organs, plays a critical role in lymphoid homeostasis. Foxo3a deficiency leads to spontaneous lymphoproliferation, associated with inflammation of several organs, in the absence of overt apoptotic defects. These findings correlated with the presence of hyperactivated helper T cells, which proliferated more vigorously and produced more Th1 and Th2 cytokines than their wild-type counterparts. Foxo3a inhibits NF-kappaB activation, whose overactivity was responsible for T cell hyperactivity in Foxo3a-deficient mice. Thus, Foxo3a regulates helper T cell activation and tolerance by inhibiting NF-kappaB activity, reinforcing a generalized role for the forkhead proteins in the maintenance of T cell tolerance through the inhibition of inflammatory transcriptional activities.
Division of Rheumatology, Department of Internal Medicine, 660 South Euclid Avenue, Saint Louis, Missouri 63110, USA.
Ling
L
Lin
Jonathan D
JD
Hron
Stanford L
SL
Peng
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D015551:Autoimmunity / Q000276:immunology* / Q000502:physiology; D002455:Cell Division / Q000276:immunology / Q000502:physiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D016328:NF-kappa B; D014157:Transcription Factors