TY - JOUR
T1 - Histone deacetylase 3 represses cholesterol efflux during CD4+ T-cell activation
AU - Wilfahrt, Drew
AU - Philips, Rachael L.
AU - Lama, Jyoti
AU - Kizerwetter, Monika
AU - Shapiro, Michael Jeremy
AU - McCue, Shaylene A.
AU - Kennedy, Madeleine M.
AU - Rajcula, Matthew J.
AU - Zeng, Hu
AU - Shapiro, Virginia Smith
N1 - Publisher Copyright:
© Wilfahrt et al.
PY - 2021/12
Y1 - 2021/12
N2 - After antigenic activation, quiescent naive CD4+ T cells alter their metabolism to roliferate. 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.
AB - After antigenic activation, quiescent naive CD4+ T cells alter their metabolism to roliferate. 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.
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U2 - 10.7554/eLife.70978
DO - 10.7554/eLife.70978
M3 - Article
C2 - 34854376
AN - SCOPUS:85122396114
SN - 2050-084X
VL - 10
JO - eLife
JF - eLife
M1 - e70978
ER -