Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism
Open Access
- 16 March 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (11), 6056-6066
- https://doi.org/10.1073/pnas.1919893117
Abstract
T helper (Th) cells are CD4(+) effector T cells that play a critical role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach, we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor ROR gamma t during Th17 differentiation. In mature Th17 cells, GSK-J4 induces an altered transcriptional program with a profound metabolic reprogramming and concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single-cell analysis reveals a specific shift from highly inflammatory cell subsets toward a resting state upon demethylase inhibition. The root cause of the observed antiinflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1. Overall, this leads to reduced mitochondrial biogenesis, resulting in a metabolic switch with concomitant antiinflammatory effects. These data are consistent with an effect of GSK-J4 on Th17 T cell differentiation pathways directly related to proliferation and include regulation of effector cytokine profiles. This suggests that inhibiting KDM6 demethylases may be an effective, even in the short term, therapeutic target for autoimmune diseases, including ankylosing spondylitis.Funding Information
- Arthritis Research UK (20522)
- Fondation Leducq (LEAN)
This publication has 87 references indexed in Scilit:
- The H3K27 Demethylase JMJD3 Is Required for Maintenance of the Embryonic Respiratory Neuronal Network, Neonatal Breathing, and SurvivalCell Reports, 2012
- Small molecule inhibitors of RORγt: Targeting Th17 cells and other applicationsEuropean Journal of Immunology, 2012
- Inflammasomes in carcinogenesis and anticancer immune responsesNature Immunology, 2012
- The Transcription Factor Myc Controls Metabolic Reprogramming upon T Lymphocyte ActivationImmunity, 2011
- Jmjd3 and UTX Play a Demethylase-Independent Role in Chromatin Remodeling to Regulate T-Box Family Member-Dependent Gene ExpressionMolecular Cell, 2010
- Critical Regulation of Early Th17 Cell Differentiation by Interleukin-1 SignalingImmunity, 2009
- Global Mapping of H3K4me3 and H3K27me3 Reveals Specificity and Plasticity in Lineage Fate Determination of Differentiating CD4+ T CellsImmunity, 2009
- The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to Inhibition of Polycomb-Mediated Gene SilencingCell, 2007
- Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cellsNature, 2006
- Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brainNature, 2003