PGAM1 hypomethylation drives aerobic glycolysis in CD4 T cells to facilitate the host defense against tuberculosis

Abstract

Abstract Background DNA methylation is important epigenetic mechanism that mediates cellular development and function, but whether DNA methylation is involved in regulating CD4 T cells in the context of tuberculosis (TB) is unclear. Results We used oxidative bisulfite sequencing to measure global DNA methylation levels in isolated CD4 T cells from patients with tuberculous pleuritis (TP), latent TB infection (LTBI) and healthy controls (HC). Compared to peripheral blood mononuclear cells (PBMCs), CD4 T cells from pleural fluid mononuclear cells (PFMCs) showed a significant different global DNA methylation profile, with much lower 5-methylcytosine levels in PFMC. A signature of 376 differentially methylated regions could discriminate between TP PBMC and PFMC T cells, including hypermethylated LAPTM5, FAM134B and FOXP1, and hypomethylated CCL5, TNF and AIM2 in PFMCs. KEGG pathway analysis showed that numerous metabolic pathways, especially ‘Carbon metabolism’, were highly enriched among the differentially methylated genes with lower methylation levels in TP PFMCs. Hypomethylation of the glycolytic enzyme PGAM1 promoted gene expression and increased aerobic glycolysis in CD4 T cells to permit CD4 T-cell proliferation and effector function. Conclusions Diminished DNA methylation levels —especially in genes involved in metabolism —are an important CD4 T-cell signature at the site of infection in TB. DNA hypomethylation of PGAM1is critical mechanism in regulating the CD4 T-cell immune response by enhancing aerobic glycolysis. These findings provide novel insights into the epigenetic regulation of CD4 T-cell responses and identify potential targets for immunotherapy in TB.