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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. [ABSTRACT FROM AUTHOR]

CD8 expression in T lymphocytes is tightly regulated by the activity of at least six Cd8 enhancers (E8I-E8VI), however their complex developmental stage-, subset-, and lineage-specific interplays are incompletely understood. Here we analyzed ATAC-seq data on the Immunological Genome Project database and identified a similar developmental regulation of chromatin accessibility of a subregion of E8I, designated E8I-core, and of E8VI. Loss of E8I-core led to a similar reduction in CD8 expression in naïve CD8+ T cells and in IELs as observed in E8 I −/− mice, demonstrating that we identified the core enhancer region of E8I. While E8 VI −/− mice displayed a mild reduction in CD8 expression levels on CD8SP thymocytes and peripheral CD8+ T cells, CD8 levels were further reduced upon combined deletion of E8I-core and E8VI. Moreover, activated E8 I - core−/− E8 VI −/− CD8+ T cells lost CD8 expression to a greater degree than E8 I - core−/− and E8 VI −/− CD8+ T cells, suggesting that the combined activity of both enhancers is required for establishment and maintenance of CD8 expression before and after TCR activation. Finally, we observed a severe reduction of CD4 CTLs among the TCRβ+CD4+ IEL population in E8 I - core−/− but not E8 VI −/− mice. Such a reduction was not observed in Cd8a −/− mice, indicating that E8I-core controls the generation of CD4 CTLs independently of its role in Cd8a gene regulation. Further, the combined deletion of E8I-core and E8VI restored CD4 CTL subsets, suggesting an antagonistic function of E8VI in the generation of CD4 CTLs. Together, our study demonstrates a complex utilization and interplay of E8I-core and E8VI in regulating CD8 expression in cytotoxic lineage T cells and in IELs. Moreover, we revealed a novel E8I-mediated regulatory mechanism controlling the generation of intestinal CD4 CTLs. [ABSTRACT FROM AUTHOR]

FOXP3 + regulatory T cells (Treg cells) are key for immune homeostasis. Here, we reveal that nuclear receptor corepressor 1 (NCOR1) controls naïve and effector Treg cell states. Upon NCOR1 deletion in T cells, effector Treg cell frequencies were elevated in mice and in in vitro-generated human Treg cells. NCOR1-deficient Treg cells failed to protect mice from severe weight loss and intestinal inflammation associated with CD4 + T cell transfer colitis, indicating impaired suppressive function. NCOR1 controls the transcriptional integrity of Treg cells, since effector gene signatures were already upregulated in naïve NCOR1-deficient Treg cells while effector NCOR1-deficient Treg cells failed to repress genes associated with naïve Treg cells. Moreover, genes related to cholesterol homeostasis including targets of liver X receptor (LXR) were dysregulated in NCOR1-deficient Treg cells. However, genetic ablation of LXRβ in T cells did not revert the effects of NCOR1 deficiency, indicating that NCOR1 controls naïve and effector Treg cell subset composition independent from its ability to repress LXRβ-induced gene expression. Thus, our study reveals that NCOR1 maintains naïve and effector Treg cell states via regulating their transcriptional integrity. We also reveal a critical role for this epigenetic regulator in supporting the suppressive functions of Treg cells in vivo., Competing Interests: VS, Rd, RR, CZ, TP, PH, DH, MA, LM, MW, DW, AH, BA, MS, TF, TK, SK, CC, KS, MT, AB, CB, NB, WE No competing interests declared, (© 2024, Stolz, de Freitas e Silva et al.)

Background & Aims: 24-Norursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid used to treat immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC), where dysregulated T cells including CD8 + T cells contribute to hepatobiliary immunopathology. We hypothesized that NorUDCA may directly modulate CD8 + T cell function thus contributing to its therapeutic efficacy., Methods: NorUDCA's immunomodulatory effects were first studied in Mdr2 -/- mice, as a cholestatic model of PSC. To differentiate NorUDCA's immunomodulatory effects on CD8 + T cell function from its anticholestatic actions, we also used a non-cholestatic model of hepatic injury induced by an excessive CD8 + T cell immune response upon acute non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Studies included molecular and biochemical approaches, flow cytometry and metabolic assays in murine CD8 + T cells in vitro. Mass spectrometry was used to identify potential CD8 + T cell targets modulated by NorUDCA. The signaling effects of NorUDCA observed in murine cells were validated in circulating T cells from patients with PSC., Results: NorUDCA demonstrated immunomodulatory effects by reducing hepatic innate and adaptive immune cells, including CD8 + T cells in the Mdr2 -/- model. In the non-cholestatic model of CD8 + T cell-driven immunopathology induced by acute LCMV infection, NorUDCA ameliorated hepatic injury and systemic inflammation. Mechanistically, NorUDCA demonstrated strong immunomodulatory efficacy in CD8 + T cells affecting lymphoblastogenesis, expansion, glycolysis and mTORC1 signaling. Mass spectrometry identified that NorUDCA regulates CD8 + T cells by targeting mTORC1. NorUDCA's impact on mTORC1 signaling was further confirmed in circulating PSC CD8 + T cells., Conclusions: NorUDCA has a direct modulatory impact on CD8 + T cells and attenuates excessive CD8 + T cell-driven hepatic immunopathology. These findings are relevant for treatment of immune-mediated liver diseases such as PSC., Lay Summary: Elucidating the mechanisms by which 24-norursodeoxycholic acid (NorUDCA) works for the treatment of immune-mediated liver diseases, such as primary sclerosing cholangitis, is of considerable clinical interest. Herein, we uncovered an unrecognized property of NorUDCA in the immunometabolic regulation of CD8 + T cells, which has therapeutic relevance for immune-mediated liver diseases, including PSC., Competing Interests: Conflict of interest M. Trauner has served as speaker for Falk Foundation, Gilead, Intercept and MSD; he has advised for Albireo, BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Intercept, Jannsen, MSD, Novartis, Phenex, Regulus and Shire. He further received travel grants from Abbvie, Falk, Gilead and Intercept and research grants from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD Takeda and UltraGenyx. He is also co-inventor of patents on the medical use of NorUDCA filed by the Medical Universities of Graz and Vienna. All the other authors declare no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

CD4 + T cell trafficking is a fundamental property of adaptive immunity. In this study, we uncover a novel role for histone deacetylase 1 (HDAC1) in controlling effector CD4 + T cell migration, thereby providing mechanistic insight into why a T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis (EAE). HDAC1-deficient CD4 + T cells downregulated genes associated with leukocyte extravasation. In vitro, HDAC1-deficient CD4 + T cells displayed aberrant morphology and migration on surfaces coated with integrin LFA-1 ligand ICAM-1 and showed an impaired ability to arrest on and to migrate across a monolayer of primary mouse brain microvascular endothelial cells under physiological flow. Moreover, HDAC1 deficiency reduced homing of CD4 + T cells into the intestinal epithelium and lamina propria preventing weight-loss, crypt damage and intestinal inflammation in adoptive CD4 + T cell transfer colitis. This correlated with reduced expression levels of LFA-1 integrin chains CD11a and CD18 as well as of selectin ligands CD43, CD44 and CD162 on transferred circulating HDAC1-deficient CD4 + T cells. Our data reveal that HDAC1 controls T cell-mediated autoimmunity via the regulation of CD4 + T cell trafficking into the CNS and intestinal tissues., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2020 Hainberger, Stolz, Zhu, Schuster, Müller, Hamminger, Rica, Waltenberger, Alteneder, Krausgruber, Hladik, Knapp, Bock, Trauner, Farrar and Ellmeier.)

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, MAZR-deficient 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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

CD8 expression in T lymphocytes is tightly regulated by the activity of at least six Cd8 enhancers (E8 I -E8 VI ), however their complex developmental stage-, subset-, and lineage-specific interplays are incompletely understood. Here we analyzed ATAC-seq data on the Immunological Genome Project database and identified a similar developmental regulation of chromatin accessibility of a subregion of E8 I , designated E8 I -core, and of E8 VI . Loss of E8 I -core led to a similar reduction in CD8 expression in naïve CD8 + T cells and in IELs as observed in E8 I -/- mice, demonstrating that we identified the core enhancer region of E8 I . While E8 VI -/- mice displayed a mild reduction in CD8 expression levels on CD8SP thymocytes and peripheral CD8 + T cells, CD8 levels were further reduced upon combined deletion of E8 I -core and E8 VI . Moreover, activated E8 I - core -/- E8 VI -/- CD8 + T cells lost CD8 expression to a greater degree than E8 I - core -/- and E8 VI -/- CD8 + T cells, suggesting that the combined activity of both enhancers is required for establishment and maintenance of CD8 expression before and after TCR activation. Finally, we observed a severe reduction of CD4 CTLs among the TCRβ + CD4 + IEL population in E8 I - core -/- but not E8 VI -/- mice. Such a reduction was not observed in Cd8a -/- mice, indicating that E8 I -core controls the generation of CD4 CTLs independently of its role in Cd8a gene regulation. Further, the combined deletion of E8 I -core and E8 VI restored CD4 CTL subsets, suggesting an antagonistic function of E8 VI in the generation of CD4 CTLs. Together, our study demonstrates a complex utilization and interplay of E8 I -core and E8 VI in regulating CD8 expression in cytotoxic lineage T cells and in IELs. Moreover, we revealed a novel E8 I -mediated regulatory mechanism controlling the generation of intestinal CD4 CTLs.