eLife (Dec 2021)

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

  • Drew Wilfahrt,
  • Rachael L Philips,
  • Jyoti Lama,
  • Monika Kizerwetter,
  • Michael Jeremy Shapiro,
  • Shaylene A McCue,
  • Madeleine M Kennedy,
  • Matthew J Rajcula,
  • Hu Zeng,
  • Virginia Smith Shapiro

DOI
https://doi.org/10.7554/eLife.70978
Journal volume & issue
Vol. 10

Abstract

Read online

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.

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