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

eLife

Matthew J Rajcula¹  Rachael L Philips¹  Shaylene A McCue¹  Madeleine M Kennedy¹  Monika Kizerwetter¹  Jyoti Lama¹  Drew Wilfahrt¹  Virginia Smith Shapiro¹  Michael Jeremy Shapiro¹  Hu Zeng² 

[1] Department of Immunology, Mayo Clinic, Rochester, United States;Department of Immunology, Mayo Clinic, Rochester, United States;Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, United States;

关键词: HDAC3;    T cell activation;    cholesterol regulation;    Mouse;   

DOI  :  10.7554/eLife.70978

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY