AMPK signaling downstream of adenosine 2A receptor represses Th17 cell pathogenicity through epigenetic and metabolic reprogramming.

Metabolic reprogramming controls protective or pathogenic Th17 cell responses; still, the precise molecular pathways that drive distinct immunometabolic states remain elusive. Here, we demonstrate that non-pathogenic Th17 cells induced by the immunoregulatory cytokine activin- A display reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). Notably, signaling through the adenosine A 2A receptor (A 2A R)/AMP-activated protein kinase (AMPK) axis in response to activin-A, boosts OXPHOS and reprograms pathogenic Th17 cells towards non-pathogenic states. Epigenetic studies revealed that pathogenic Th17 cells express highly the CBP/P300 binding protein (PCAF) which facilitates the acetylation of histone 3 at lysine 9 (H3K9ac) at genes related to the mammalian target of rapamycin complex 1 (mTORC1), glycolysis and Th17 pathogenicity programs. Instead, activin-A-treated Th17 cells display an AMPK-mediated suppression of PCAF activity and aerobic metabolism while, accumulate H3K9ac in gene loci related to OXPHOS. Collectively, we uncover A 2A R-AMPK as a central metabolic checkpoint that epigenetically regulates Th17 pathogenicity. We performed H3K9ac and PCAF ChIP-seq in pathogenic and non-pathogenic Th17 cells induced in the absence or presence of Activin-A, respectively.