Critical role of the tumor suppressor tuberous sclerosis complex 1 in dendritic cell activation of CD4 T cells by promoting MHC class II expression via IRF4 and CIITA.
Critical role of the tumor suppressor tuberous sclerosis complex 1 in dendritic cell activation of CD4 T cells by promoting MHC class II expression via IRF4 and CIITA.
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DOI：
10.4049/jimmunol.1201443
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发表时间：
2013-07-15
期刊：
影响因子：
--
通讯作者：
Zhong XP
中科院分区：
文献类型：
--
作者：
Pan H;O'Brien TF;Wright G;Yang J;Shin J;Wright KL;Zhong XP
Dendritic cell (DC) maturation is characterized by upregulation cell surface MHC class II (MHCII) and costimulatory molecules and production of a variety of cytokines that can shape both innate and adaptive immunity. Paradoxically, transcription of the MHCII genes as well as its activator, CIITA, is rapidly silenced during DC maturation. The mechanisms that control CIITA/MHCII expression and silencing have been not fully understood. We report here that the tumor suppressor TSC1 is a critical regulator of DC function for both innate and adaptive immunity. Its deficiency in DCs results in increased mTOR complex 1 (mTORC1) but decreased mTORC2 signaling, altered cytokine production, impaired CIITA/MHCII expression, and defective antigen presentation to CD4 T cells following TLR4 stimulation. We demonstrate further that IRF4 can directly bind to CIITA promoters and decreased IRF4 expression is partially responsible for decreased CIITA/MHC-II expression in TSC1 deficient DCs. Moreover, we identify that CIITA/MHCII silencing during DC maturation requires mTORC1 activity. Together, our data reveal unexpected roles of TSC1/mTOR that control multifaceted functions of DCs.
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