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Forkhead box protein P3 + (FOXP3 + ) regulatory T cells (T reg cells) play a key role in maintaining tolerance and immune homeostasis. Here, we report that a T cell-specific deletion of the transcription factor MAZR (also known as PATZ1) leads to an increased frequency of T reg cells, while enforced MAZR expression impairs T reg cell differentiation. Further, MAZR expression levels are progressively downregulated during thymic T reg cell development and during in-vitro-induced human T reg cell differentiation, suggesting that MAZR protein levels are critical for controlling T reg cell development. However, MAZRdeficient T reg cells show only minor transcriptional changes ex vivo, indicating that MAZR is not essential for establishing the transcriptional program of peripheral T reg cells. Finally, the loss of MAZR reduces the clinical score in dextran-sodium sulfate (DSS)-induced colitis, suggesting that MAZR activity in T cells controls the extent of intestinal inflammation. Together, these data indicate that MAZR is part of a T reg cell-intrinsic transcriptional network that modulates T reg cell development.

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.

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Invariant natural killer T (iNKT) cells represent a subgroup of innate-like T cells and play an important role in immune responses against certain pathogens. In addition, they have been linked to autoimmunity and antitumor immunity. iNKT cells consist of several subsets with distinct functions; however, the transcriptional networks controlling iNKT subset differentiation are still not fully characterized. Myc-associated zinc-finger-related factor (MAZR, also known as PATZ1) is an essential transcription factor for CD8+ lineage differentiation of conventional T cells. Here, we show that MAZR plays an important role in iNKT cells. T-cell lineage-specific deletion of MAZR resulted in an iNKT cell-intrinsic defect that led to an increase in iNKT2 cell numbers, concurrent with a reduction in iNKT1 and iNKT17 cells. Consistent with the alteration in the subset distribution, deletion of MAZR also resulted in an increase in the percentage of IL-4-producing cells. Moreover, MAZR-deficient iNKT cells displayed an enhanced expression of Erg2 and ThPOK, key factors for iNKT cell generation and subset differentiation, indicating that MAZR controls iNKT cell development through fine-tuning of their expression levels. Taken together, our study identified MAZR as an essential transcription factor regulating iNKT cell subset differentiation and effector function.Electronic supplementary materialThe online version of this article (10.1007/s00018-019-03119-z) contains supplementary material, which is available to authorized users.