Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism

Through discovery and mechanistic characterization of a small molecule, -acetic acid, that reprograms TH17 differentiation toward iTreg cells, we show increased transamination mainly via Got1 leads to elevated 2-hydroxyglutarate level in differentiating TH17 cells

Tao Xu; Kelly M. Stewart; Xiaohu Wang; Kai Liu; Min Xie; Jae Kyu Ryu; Ke Li; Tianhua Ma; Haixia Wang; Lu Ni; Saiyong Zhu; Nan Cao; Dongwei Zhu; Yu Zhang; Katerina Akassoglou; Chen Dong; Edward M. Driggers; Sheng Ding


Scholarcy highlights

  • Metabolism has been shown to integrate with epigenetics and transcription to modulate cell fate and function
  • To identify small molecules that reprogram TH17 differentiation toward iTreg cell fate, we screened 10,000 small molecules using CD4+ naïve T cells from IL-17F-RFP/FOXP3-GFP mice cultured under optimal TH17 differentiation conditions 11
  • AOA treated TH17 cells had a similar slow proliferation rate as iTreg cells; the effect of AOA on cell proliferation did not impair cell survival or the ability of these T cells to differentiate into iTreg cells under TH17 differentiation condition
  • AOA selectively reduced the mRNA level of Il17/Il17f, but not Rorc in TH17 cells and promoted transcription of FOXP3 in TH17 and iTreg cells
  • Tet1/2 DKO partially diminished the effect of AOA on TH17 cell differentiation, possibly due to that all three Tet proteins function redundantly to regulate FOXP3 expression
  • AOA treatment increased 5hmC signal at both FOXP3 promoter and CNS2 region, decreased 5mC signal at FOXP3 promoter, but not the CNS2 region, likely because the changes were too subtle and not detectable as CNS2 region is always hypermethylated in iTreg cell
  • The percentage of IL-17 producing T cells and FOXP3+Treg cells infiltrating into central nervous system were significantly decreased and increased, respectively by Got knockdown, while IFNү+ T cells were not readily detectable

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