TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity.
Regulatory T cells (Tregs) maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR). T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO) mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 (+) Tregs into Rag2(-/-) mice revealed that TRAF6-deficient Tregs converted into Foxp3(-) cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3(+) to Foxp3(-) (exFoxp3 cells) was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs.
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
Go
G
Muto
Hitoshi
H
Kotani
Taisuke
T
Kondo
Rimpei
R
Morita
Sanae
S
Tsuruta
Takashi
T
Kobayashi
Hervé
H
Luche
Hans Joerg
HJ
Fehling
Matthew
M
Walsh
Yongwon
Y
Choi
Akihiko
A
Yoshimura
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D050799:STAT5 Transcription Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D050799:STAT5 Transcription Factor; D048029:TNF Receptor-Associated Factor 6; C045073:Cre recombinase; D019426:Integrases