REGγ controls Th17 cell differentiation and autoimmune inflammation by regulating dendritic cells

Abstract

Interleukin-17A (IL-17A)-producing helper T (Th17) cells are a subset of CD4+ T cells that play important pathological roles in autoimmune diseases. Although the intrinsic pathways of Th17 cell differentiation have been well described, how instructive signals derived from the innate immune system trigger the Th17 response and inflammation remains poorly understood. Here, we report that mice deficient in REGγ, a proteasome activator belonging to the 11S family, exhibit significantly deteriorated autoimmune neuroinflammation in an experimental autoimmune encephalomyelitis (EAE) model with augmented Th17 cell polarization in vivo. The results of the adoptive transfer of CD4+ T cells or dendritic cells (DCs) suggest that this phenotype is driven by DCs rather than T cells. Furthermore, REGγ deficiency promotes the expression of integrin αvβ8 on DCs, which activates the maturation of TGF-β1 to enhance Th17 cell development. Mechanistically, this process is mediated by the REGγ-proteasome-dependent degradation of IRF8, a transcription factor for αvβ8. Collectively, our findings delineate a previously unknown mechanism by which REGγ-mediated protein degradation in DCs controls the differentiation of Th17 cells and the onset of an experimental autoimmune disease.

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Acknowledgements

We thank Dr. Nan Shen for providing CD11c-DTR mice, Dr. Hongyan Wang for providing OT-II mice, and Dr. Stephen L. Nishimura for providing anti-αvβ8 neutralizing antibody. We also thank the ECNU Multifunctional Platform for Innovation (011) for maintaining and raising the mice. This work was supported by the National Program on Key Basic Research Project (2015CB901402), the National Natural Science Foundation of China (31670882, 31730017, 81672883), the Science and Technology Commission of Shanghai Municipality (16ZR1410000, 16QA1401500), and the Foundation of Guangdong Second Provincial General Hospital (2017-001).

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L.Z., X.L. and B.Z. designed the research. L.Z., L.Y. and Q.Z. performed most molecular, cell biology, immunological, and animal experiments. W.X., X.W., J.X., Q.L., Q.L., Y.X., H.Z., L.J., L.W., Weicang Wang, Weichao Wang, and T.S. helped with the experiments. L.F., B.Z., S.L. and L.L. provided scientific advice and valuable expertise. XT.L., B.Z. and L.Z. wrote the manuscript with input from all the authors.

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Correspondence to Lei Li or Shuang Liu or Bianhong Zhang or Xiaotao Li.

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The authors declare no competing interests.

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Zhou, L., Yao, L., Zhang, Q. et al. REGγ controls Th17 cell differentiation and autoimmune inflammation by regulating dendritic cells. Cell Mol Immunol 17, 1136–1147 (2020). https://doi.org/10.1038/s41423-019-0287-0

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Key words

  • REGγ
  • EAE
  • DC
  • TGF-β
  • Th17

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