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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.

Publication ,  Journal Article
Pan, H; O'Brien, TF; Wright, G; Yang, J; Shin, J; Wright, KL; Zhong, X-P
Published in: J Immunol
July 15, 2013

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.

Duke Scholars

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

July 15, 2013

Volume

191

Issue

2

Start / End Page

699 / 707

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 1 Protein
  • Trans-Activators
  • Toll-Like Receptor 4
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • RNA, Small Interfering
  • RNA Interference
  • Proteins
  • Promoter Regions, Genetic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Pan, H., O’Brien, T. F., Wright, G., Yang, J., Shin, J., Wright, K. L., & Zhong, X.-P. (2013). 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. J Immunol, 191(2), 699–707. https://doi.org/10.4049/jimmunol.1201443
Pan, Hongjie, Thomas F. O’Brien, Gabriela Wright, Jialong Yang, Jinwook Shin, Kenneth L. Wright, and Xiao-Ping Zhong. “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.J Immunol 191, no. 2 (July 15, 2013): 699–707. https://doi.org/10.4049/jimmunol.1201443.
Pan, Hongjie, et al. “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.J Immunol, vol. 191, no. 2, July 2013, pp. 699–707. Pubmed, doi:10.4049/jimmunol.1201443.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

July 15, 2013

Volume

191

Issue

2

Start / End Page

699 / 707

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 1 Protein
  • Trans-Activators
  • Toll-Like Receptor 4
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • RNA, Small Interfering
  • RNA Interference
  • Proteins
  • Promoter Regions, Genetic