Abstract
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.
Highlights
After activation, CD4+ T cells must pass through a number of metabolic checkpoints in order to proliferate, differentiate, and generate robust immune responses
Cre recombinase expression is driven by the distal promoter of lymphocyte- specific protein tyrosine kinase (Lck)
Given the incongruence of Histone deacetylase 3 (HDAC3) deletion between the naive and memory CD4+ T-cell populations in the dLck-Cre HDAC3 cKO, we examined whether HDAC3 could play a role in the formation and expansion of memory CD4+ T cells
Summary
CD4+ T cells must pass through a number of metabolic checkpoints in order to proliferate, differentiate, and generate robust immune responses This metabolic transition shortly after TCR engagement has been defined as quiescence exit, and is characterized by several key cellular events including cell growth, interleukin-2 (IL-2) signaling, increased anabolic metabolism, and reprogramming of mitochondrial metabolism (Chapman et al, 2019; Chapman and Chi, 2018; Ron-Harel et al, 2016; Tan et al, 2017; Wang et al, 2011; Yang et al, 2013). Our understanding of the transcriptional control of CD4+ T cells exiting quiescence is incomplete
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