Acly promotes metabolic reprogramming and induction of IRF4 during early CD8+ T cell activation

Abstract

CD8⁺ T cells, a fundamental part of the adaptive immune system, employ cytotoxic responses important for targeting pathogenic bacteria, viruses, and tumor cells. During early activation, CD8⁺ T cells undergo many changes in metabolism and gene expression. The bridge between epigenetic and metabolic influences on gene expression and cell fate has yet to be fully understood. Here, we investigated the importance of ATP citrate lyase (Acly), an enzyme involved in both metabolism and histone acetylation, for early stages of CD8⁺ T cell activation. We performed polyclonal activation of murine CD8⁺ T cells in vitro in the presence or absence of the Acly inhibitor BMS303141. We found that inhibiting Acly during early activation results in decreased expression of early activation markers. Consistent with impaired early activation, we found that inhibition also resulted in increased uptake of fatty acids and decreased glucose uptake without changing mitochondrial ATP levels. On an epigenetic and transcriptional level, early stage Acly inhibition specifically downregulated promoter histone H3 acetylation (H3ac) and expression of the key transcription factor IRF4; however, global levels of H3ac remained similar. Most importantly, the study was able to highlight the importance of Acly in early stages of CD8⁺ T cell activation and histone regulation.

Keywords: Acly; CD8+ T cells; IRF4.