Histone deacetylase 3 represses cholesterol efflux during CD4 + T-cell activation

• Published in: eLife Vol. 10
• Main Authors: Wilfahrt, Drew, Philips, Rachael L, Lama, Jyoti, Kizerwetter, Monika, Shapiro, Michael Jeremy, McCue, Shaylene A, Kennedy, Madeleine M, Rajcula, Matthew J, Zeng, Hu, Shapiro, Virginia Smith
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 02-12-2021; eLife Sciences Publications, Ltd
• Subjects: ABCA1 protein; Animals; ATP Binding Cassette Transporter 1 - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 1 - metabolism; ATP-binding protein; CD28 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; Cell activation; Cholesterol; Cholesterol - genetics; Cholesterol - metabolism; cholesterol regulation; Experiments; Fatty acids; Female; Gene expression; Gene silencing; HDAC3; Histone deacetylase; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Homeostasis; Immunology and Inflammation; Kinases; Lipids; Lymphocytes; Lymphocytes T; Male; Metabolism; Metabolites; Mice; Mice, Mutant Strains; Nucleotides; Population; Proteins; Standard deviation; Sterols; T cell activation; T cell receptors; Thymus gland; Transcription activation; Transcription factors; Variance analysis; mouse; HDAC3; T cell activation; cholesterol regulation; inflammation; immunology
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.70978

After antigenic activation, quiescent naive CD4
T cells alter their metabolism to proliferate. This metabolic shift increases production of nucleotides, amino acids, fatty acids, and sterols. Here, we show that histone deacetylase 3 (HDAC3) is critical for activation of murine peripheral CD4
T cells. HDAC3-deficient CD4
T cells failed to proliferate and blast after in vitro TCR/CD28 stimulation. Upon T-cell activation, genes involved in cholesterol biosynthesis are upregulated while genes that promote cholesterol efflux are repressed. HDAC3-deficient CD4
T cells had reduced levels of cellular cholesterol both before and after activation. HDAC3-deficient cells upregulate cholesterol synthesis appropriately after activation, but fail to repress cholesterol efflux; notably, they overexpress cholesterol efflux transporters ABCA1 and ABCG1. Repression of these genes is the primary function for HDAC3 in peripheral CD4
T cells, as addition of exogenous cholesterol restored proliferative capacity. Collectively, these findings demonstrate HDAC3 is essential during CD4
T-cell activation to repress cholesterol efflux.