The differentiation of naïve CD4+ T cells into T helper (Th) subsets is key for a functional immune response and has to be tightly controlled by transcriptional and epigenetic processes. However, the function of cofactors that connect gene-specific transcription factors with repressive chromatin-modifying enzymes in Th cells is yet unknown. Here we demonstrate an essential role for nuclear receptor corepressor 1 (NCOR1) in regulating naïve CD4+ T cell and Th1/Th17 effector transcriptomes. Moreover, NCOR1 binds to a conserved cis-regulatory element within the Ifng locus and controls the extent of IFNγ expression in Th1 cells. Further, NCOR1 controls the survival of activated CD4+ T cells and Th1 cells in vitro, while Th17 cell survival was not affected in the absence of NCOR1. In vivo, effector functions were compromised since adoptive transfer of NCOR1-deficient CD4+ T cells resulted in attenuated colitis due to lower frequencies of IFNγ+ and IFNγ+IL-17A+ Th cells and overall reduced CD4+ T cell numbers. Collectively, our data demonstrate that the coregulator NCOR1 shapes transcriptional landscapes in CD4+ T cells and controls Th1/Th17 effector functions.
Bibliographical noteFunding Information:
We thank Johan Auwerx for providing floxed-Ncor1 mutant mice and Shinya Sakaguchi and Nicole Boucheron for critical reading of the manuscript. Further we thank Claus Wenhardt for assistance with cell sorting. Funding. This work was supported by the following grants: Austrian Science Fund (FWF) and MedUni Vienna doctoral program (DK W1212) Inflammation and Immunity (to WE and MT); FWF projects P19930, P23641, and P26193 (WE); FWF doc.fund program TissueHome (WE); FWF Special Research Program F70 (F07002 to CB and F07005 to WE); NIH grant R01 AI147540 (MF). DH received a L'Oréal Austria Fellowship supported by the Austrian Commission for UNESCO in cooperation with the Austrian Academy of Sciences. PH was supported by a DOC fellowship of the Austrian Academy of Sciences.
© Copyright © 2020 Hainberger, Stolz, Zhu, Schuster, Müller, Hamminger, Rica, Waltenberger, Alteneder, Krausgruber, Hladik, Knapp, Bock, Trauner, Farrar and Ellmeier.
- CD4 T cells
- T helper differentiation
- gene regulation
- interferon γ