Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation

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Date: Nov. 2, 2017
From: Nature(Vol. 551, Issue 7678)
Publisher: Nature Publishing Group
Document Type: Report
Length: 7,246 words
Lexile Measure: 1470L

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Author(s): Song Zhang [1, 2]; Motoki Takaku [3]; Liyun Zou [1, 2]; Ai-di Gu [1, 2]; Wei-chun Chou [1, 2, 4]; Ge Zhang [1, 2, 5]; Bing Wu [1, 2]; Qing Kong [1, 2, 6]; Seddon Y. Thomas [7]; Jonathan S. Serody [1, 2]; Xian Chen [1, 6]; Xiaojiang Xu [8]; Paul A. Wade [3]; Donald N. Cook [7]; Jenny P. Y. Ting [1, 2, 4]; Yisong Y. Wan (corresponding author) [1, 2]

T helper 17 (TH 17) cells are critically involved in host defence, inflammation, and autoimmunity [1, 2, 3, 4, 5]. Transforming growth factor (TGF) is instrumental in TH 17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGF enables TH 17 cell differentiation remains elusive. Here we reveal that TGF enables T H 17 cell differentiation by reversing SKISMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor t (RORt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH 17 cells in the absence of TGF signalling in a RORt-dependent manner. Ectopic SMAD4 expression suppresses RORt expression and TH 17 cell differentiation of SMAD4-deficient T cells. However, TGF neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGF stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH 17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH 17 cell differentiation in a SMAD4-dependent manner. Therefore, TGF-induced disruption of SKI reverses SKISMAD4-mediated suppression of RORt to enable T H 17 cell differentiation. This study reveals a critical mechanism by which TGF controls TH 17 cell differentiation and uncovers the SKISMAD4 axis as a potential therapeutic target for treating TH 17-related diseases.

We studied the mechanisms underlying the important role of TGF signalling in TH 17 cell differentiation [6, 7, 8, 9, 10]. We found that CD4+ T cells from wild-type and Cd4-cre;Smad4 fl /fl (S4 knockout) mice [11] differentiated into TH 17 cells comparably in the presence of interleukin (IL)-6 and TGF, as reported previously [12]. However, in stark contrast to wild-type T cells, SMAD4-deficient T cells consistently differentiated into TH 17 cells when provided with IL-6 alone without TGF (Fig. 1a). This observation prompted us to hypothesize that SMAD4 deletion may result in T H 17 cell differentiation in the absence of TGF signalling. To test this hypothesis, we blocked TGF signalling by using a pharmacological inhibitor of TGF receptor (TGFR) kinase activity. Whereas wild-type T cells did not become TH 17 cells, SMAD4-deficient T cells readily differentiated into TH 17 cells and expressed TH 17-related genes when TGF signalling was inhibited (Fig. 1a, b and Extended Data Fig. 1a). To confirm this finding and exclude the potential off-target effect of the inhibitor, we generated Cd4-cre;Smad4 fl /fl ;Tgfbr2 fl /fl (S4RII double-knockout) mice, in which both SMAD4 and TGF receptor II (TGFRII) were deleted...

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Gale Document Number: GALE|A512765827