Elucidating histone deacetylase 3 and its role in CD4 + T cell activation

By Sara Leahey

CD4 + T cells undergo a metabolic shift after activation, increasing cellular processes that make blasting and proliferation possible. A Class I histone deacetylase called histone deacetylase 3 (HDAC3) represses gene expression through the deacetylation of lysine residues on histones 3 and 4. HDAC3 has been shown to be a key regulator in gene expression for the T cell developmental pathway.

The authors worked on elucidating the role of HDAC3 in this metabolic shift of CD4 + T cells. The authors proceeded with a mouse model that uses the Cre recombinase system driven by the distal promoter of the lymphocyte-specific Lck, which results in HDAC3 being knocked out specifically in T cells. They’d found that the differentiation of CD4 + T cell subtypes are comparable in both the HDAC3-sufficient (WT) and HDAC3 knockout (KO) mice. When looking at total cell number, the HDAC3-deficient CD4 + T cells had reduced numbers compared to the WT cells, suggesting difference in proliferative capacity. Going further into this, they looked at the proliferation capacity of enriched CD4 + T cells from the HDAC3 KO mice and showed reduced viability and proliferative capacity in HDAC-deficient CD4 + T cells. The authors concluded that HDAC3 is necessary for CD4 + T cell proliferation after activation.
The authors decided to investigate mTORC1’s involvement in the metabolic switch and how it may be related to the decrease of proliferation and blasting in HDAC3-deficient CD4 + T cells. Interestingly, downstream signaling events in the mTORC1 pathway were decreased in the CD4 + T cells isolated from HDAC3 KO mice, along with decreased oxygen consumption rate (OCR). These data helped explain how HDAC3 may be affecting the proliferation of CD4 + T cells through metabolic reprogramming. To dive more into the mechanism of this metabolic reprogramming, the authors explored lipid synthesis, post-T-cell activation. It was found that not only is blasting reduced, the cholesterol levels also decreased in the HDAC3 KO CD4 + T cells, compared to the WT CD4 + T cells. The authors discovered that genes involved in cholesterol efflux, ABCA1 and ABCG1, were increased in the HDAC3 KO CD4 + T cells.
Further investigation showed that Abca1 and Abcg1 genes are hyperacetylated after loss of HDAC3, suggesting a role of HDAC3 in repressing these genes through deacetylation and thus preventing cholesterol efflux during CD4 + T cell activation and proliferation. These findings are important in our understanding of how changes in metabolic reprogramming can negatively affect T cell activation and proliferation.

A highlight and Commentary by Sara Leahey (Graduate Student) for Wilfahrt, et al., 2021: Histone deacetylase 3 represses cholesterol efflux during CD4+ T-cell
activation. eLife