Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells.
T-cell responses to a cytokine milieu instruct the development of multiple effector phenotypes. While transforming growth factor-beta(1) (TGF-beta(1)) inhibits the development of T helper type 1 (Th1) and Th2 cells, we demonstrate that like interleukin-6 (IL-6) and IL-4, IL-12 can inhibit the development of TGF-beta(1)-induced Foxp3-expressing adaptive T regulatory (aTreg) cells. Signal transducer and activator of transcription 4 (STAT4) is critical for the response to IL-12, although there is a parallel pathway involving T box expressed in T cells (T-bet), and cells from mice double-deficient in STAT4 and T-bet are refractory to the inhibition of aTreg-cell development by IL-12. While the ability of these cytokines to promote Th differentiation may contribute to this effect, we observe that culture with IL-12, or other instructive cytokines, results in an increase in repressive chromatin modifications at the Foxp3 locus that limit STAT5 binding to Foxp3, without observed effects on IL-2 signalling pathways. In a model of allergic lung inflammation there are increased percentages of Treg cells in the lungs of Stat4(-/-) mice, compared with wild-type mice, and increases in Treg cells correlate with decreased allergic inflammation. Overall, these results suggest an important role for STAT4 in regulating Treg-cell development.
O'Malley
John T
JT
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, IN 46202, USA.
Sehra
Sarita
S
Thieu
Vivian T
VT
Yu
Qing
Q
Chang
Hua-Chen
HC
Stritesky
Gretta L
GL
Nguyen
Evelyn T
ET
Mathur
Anubhav N
AN
Levy
David E
DE
Kaplan
Mark H
MH
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012130:Respiratory Hypersensitivity / Q000276:immunology; D050797:STAT4 Transcription Factor / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000276:immunology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D053773:Transforming Growth Factor beta1; D018664:Interleukin-12