Adenosine 2A receptor–dependent activation of AMPK represses T H 17 cell pathogenicity through epigenetic and metabolic reprogramming

Metabolic reprogramming controls protective and pathogenic T helper 17 (T H 17) cell responses. When naïve T cells are differentiated into T H 17 cells in vitro, the presence of the cytokine activin A promotes their maturation into a nonpathogenic state. Here, we found that nonpathogenic T H 17 cells induced by activin A displayed reduced aerobic glycolysis and increased oxidative phosphorylation (OXPHOS). In response to activin A, signaling through the adenosine A 2A receptor (A 2A R) and AMP-activated protein kinase (AMPK) enhanced OXPHOS and reprogrammed pathogenic T H 17 cells toward nonpathogenic states that did not induce central nervous system autoimmunity in a mouse model of multiple sclerosis. In pathogenic T H 17 cells, the transcriptional coactivator p300/CBP-associated factor (PCAF) increased acetylation at histone 3 Lys 9 (H3K9ac) of genes involved in aerobic glycolysis and T H 17 pathogenic programs. In contrast, in nonpathogenic activin A–treated T H 17 cells, AMPK signaling suppressed PCAF-mediated H3K9ac modification of genes involved in aerobic metabolism and enhanced H3K9ac modification of genes involved in OXPHOS and nonpathogenic T H 17 programs. Together, our findings uncover A 2A R-AMPK signaling as a central metabolic checkpoint that suppresses T H 17 cell pathogenicity.