Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation

Naive CD4 T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms that...

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Veröffentlicht in:	Proceedings of the National Academy of Sciences - PNAS Jg. 116; H. 51; S. 25839
Hauptverfasser:	Gehrmann, Ulf, Burbage, Marianne, Zueva, Elina, Goudot, Christel, Esnault, Cyril, Ye, Mengliang, Carpier, Jean-Marie, Burgdorf, Nina, Hoyler, Thomas, Suarez, Guadalupe, Joannas, Leonel, Heurtebise-Chrétien, Sandrine, Durand, Sylvère, Panes, Rébecca, Bellemare-Pelletier, Angélique, Sáez, Pablo J, Aprahamian, Fanny, Lefevre, Deborah, Adoue, Veronique, Zine El Aabidine, Amal, Muhammad Ahmad, Maqbool, Hivroz, Claire, Joffre, Olivier, Cammas, Florence, Kroemer, Guido, Gagnon, Etienne, Andrau, Jean-Christophe, Amigorena, Sebastian
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 17.12.2019
Schlagworte:	Animals Autoimmunity - physiology CD4-Positive T-Lymphocytes - metabolism Cell Differentiation - genetics Cell Differentiation - physiology Cell Plasticity - physiology Cellular Reprogramming - genetics Cellular Reprogramming - physiology Chromosomal Proteins, Non-Histone - metabolism Colon - pathology Cytokines - metabolism DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Epigenesis, Genetic - physiology Gene Expression Regulation Gene Silencing Histones - metabolism Mice Mice, Knockout Phosphatidylinositol 3-Kinases - metabolism Receptors, Antigen, T-Cell - metabolism T-Lymphocytes - metabolism T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - metabolism Transcriptome Tripartite Motif-Containing Protein 28 - genetics Tripartite Motif-Containing Protein 28 - metabolism TRIM28 autoimmunity T cells immunology epigenetics
ISSN:	1091-6490, 1091-6490
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Zusammenfassung:	Naive CD4 T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms that install and maintain these programs. Here, we use mice defective for different components of heterochromatin-dependent gene silencing to investigate the epigenetic control of CD4 T cell plasticity. We show that, upon T cell receptor (TCR) engagement, naive and regulatory T cells defective for TRIM28 (an epigenetic adaptor for histone binding modules) or for heterochromatin protein 1 β and γ isoforms (HP1β/γ, 2 histone-binding factors involved in gene silencing) fail to effectively signal through the PI3K-AKT-mTOR axis and switch to glycolysis. While differentiation of naive TRIM28 T cells into cytokine-producing effector T cells is impaired, resulting in reduced induction of autoimmune colitis, TRIM28 regulatory T cells also fail to expand in vivo and to suppress autoimmunity effectively. Using a combination of transcriptome and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses for H3K9me3, H3K9Ac, and RNA polymerase II, we show that reduced effector differentiation correlates with impaired transcriptional silencing at distal regulatory regions of a defined set of Treg-associated genes, including, for example, NRP1 or Snai3. We conclude that TRIM28 and HP1β/γ control metabolic reprograming through epigenetic silencing of a defined set of Treg-characteristic genes, thus allowing effective T cell expansion and differentiation into helper and regulatory phenotypes.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1091-6490 1091-6490
DOI:	10.1073/pnas.1901639116