TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function.
T helper cells that produce IL-17 (T(H)17 cells) promote autoimmunity in mice and have been implicated in the pathogenesis of human inflammatory diseases. At mucosal surfaces, T(H)17 cells are thought to protect the host from infection, whereas regulatory T (T(reg)) cells control immune responses and inflammation triggered by the resident microflora. Differentiation of both cell types requires transforming growth factor-beta (TGF-beta), but depends on distinct transcription factors: RORgammat (encoded by Rorc(gammat)) for T(H)17 cells and Foxp3 for T(reg) cells. How TGF-beta regulates the differentiation of T cells with opposing activities has been perplexing. Here we demonstrate that, together with pro-inflammatory cytokines, TGF-beta orchestrates T(H)17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF-beta synergizes with interleukin (IL)-6 and IL-21 (refs 9-11) to promote IL-23 receptor (Il23r) expression, favouring T(H)17 cell differentiation. High concentrations of TGF-beta repress IL23r expression and favour Foxp3+ T(reg) cells. RORgammat and Foxp3 are co-expressed in naive CD4+ T cells exposed to TGF-beta and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro, TGF-beta-induced Foxp3 inhibits RORgammat function, at least in part through their interaction. Accordingly, lamina propria T cells that co-express both transcription factors produce less IL-17 (also known as IL-17a) than those that express RORgammat alone. IL-6, IL-21 and IL-23 relieve Foxp3-mediated inhibition of RORgammat, thereby promoting T(H)17 cell differentiation. Therefore, the decision of antigen-stimulated cells to differentiate into either T(H)17 or T(reg) cells depends on the cytokine-regulated balance of RORgammat and Foxp3.
Zhou
Liang
L
The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
Lopes
Jared E
JE
Chong
Mark M W
MM
Ivanov
Ivaylo I
II
Min
Roy
R
Victora
Gabriel D
GD
Shen
Yuelei
Y
Du
Jianguang
J
Rubtsov
Yuri P
YP
Rudensky
Alexander Y
AY
Ziegler
Steven F
SF
Littman
Dan R
DR
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D018123:Receptors, Interleukin; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D016212:Transforming Growth Factor beta; C528688:interleukin-23 receptor, mouse