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.
Journal Article (Journal Article)
Dendritic cell (DC) maturation is characterized by upregulation of cell-surface MHC class II (MHC-II) and costimulatory molecules, and production of a variety of cytokines that can shape both innate and adaptive immunity. Paradoxically, transcription of the MHC-II genes, as well as its activator, CIITA, is rapidly silenced during DC maturation. The mechanisms that control CIITA/MHC-II expression and silencing have not been fully understood. We report in this article that the tumor suppressor tuberous sclerosis complex 1 (TSC1) is a critical regulator of DC function for both innate and adaptive immunity. Its deficiency in DCs results in increased mammalian target of rapamycin (mTOR) complex 1 but decreased mTORC2 signaling, altered cytokine production, impaired CIITA/MHC-II expression, and defective Ag presentation to CD4 T cells after TLR4 stimulation. We demonstrate further that IFN regulatory factor 4 can directly bind to CIITA promoters, and decreased IFN regulatory factor 4 expression is partially responsible for decreased CIITA/MHC-II expression in TSC1-deficient DCs. Moreover, we identify that CIITA/MHC-II silencing during DC maturation requires mTOR complex 1 activity. Together, our data reveal unexpected roles of TSC1/mTOR that control multifaceted functions of DCs.
Full Text
Duke Authors
Cited Authors
- Pan, H; O'Brien, TF; Wright, G; Yang, J; Shin, J; Wright, KL; Zhong, X-P
Published Date
- July 15, 2013
Published In
Volume / Issue
- 191 / 2
Start / End Page
- 699 - 707
PubMed ID
- 23776173
Pubmed Central ID
- PMC3702379
Electronic International Standard Serial Number (EISSN)
- 1550-6606
Digital Object Identifier (DOI)
- 10.4049/jimmunol.1201443
Language
- eng
Conference Location
- United States