TCR signaling induces STAT3 phosphorylation to promote Th17 cell differentiation
TCR signaling induces STAT3 phosphorylation to promote Th17 cell differentiation
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DOI：
10.1084/jem.20230683
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Tao Xu
中科院分区：
文献类型：
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作者：
Zhen Qin;Ruining Wang;Ping Hou;Yuanyuan Zhang;Qianmu Yuan;Ying Wang;Yuedong Yang;Tao Xu
TH17 differentiation is critically controlled by “signal 3” of cytokines (IL-6/IL-23) through STAT3. However, cytokines alone induced only a moderate level of STAT3 phosphorylation. Surprisingly, TCR stimulation alone induced STAT3 phosphorylation through Lck/Fyn, and synergistically with IL-6/IL-23 induced robust and optimal STAT3 phosphorylation at Y705. Inhibition of Lck/Fyn kinase activity by Srci1 or disrupting the interaction between Lck/Fyn and STAT3 by disease-causing STAT3 mutations selectively impaired TCR stimulation, but not cytokine-induced STAT3 phosphorylation, which consequently abolished TH17 differentiation and converted them to FOXP3+ Treg cells. Srci1 administration or disrupting the interaction between Lck/Fyn and STAT3 significantly ameliorated TH17 cell–mediated EAE disease. These findings uncover an unexpected deterministic role of TCR signaling in fate determination between TH17 and Treg cells through Lck/Fyn-dependent phosphorylation of STAT3, which can be exploited to develop therapeutics selectively against TH17-related autoimmune diseases. Our study thus provides insight into how TCR signaling could integrate with cytokine signal to direct T cell differentiation.
