NCOR1 Orchestrates Transcriptional Landscapes and Effector Functions of CD4+ T Cells

Abstract

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.

Keywords: CD4+ T cells; NCOR1; T helper differentiation; colitis; corepressor; gene regulation; interferon γ.