ATP citrate lyase (ACLY) regulates pro-inflammatory phenotypes in regulatory T cells in response to oxidized phospholipids 3848

Abstract Description Regulatory T cells (Tregs) protect against atherosclerosis but lose stability and function as the disease progresses. Our lab has recently identified that the oxidized phospholipid oxPAPC (oxidized 1-palmitoyl-2- arachidonoyl-sn-glycero-3-phosphocholine), enriched in atherosclerosis, induces a Th1-like, T-bet+ IFNγ+ phenotype during inducible Treg differentiation. These cells have reduced suppressive capacity in vitro and are less protective against atherosclerosis in vivo. However, the mechanism of oxPAPC-induced Treg dysfunction remains unknown. We sought to elucidate this mechanism and show that the oxPAPC-induced Th1-like phenotype depends on ATP citrate lyase (ACLY), which regulates the conversion of citrate to acetyl-CoA, a metabolite with important roles in the epigenetic regulation of IFNγ production. We found that supplementing cultures with exogenous acetate, which increases acetyl-CoA levels in an ACLY-independent manner, restores the Th1-like phenotype in Acly deficient cells differentiated with oxPAPC. This indicates ACLY may act as a link between oxPAPC and pro-inflammatory cytokine expression via acetyl-CoA regulation. A role for ACLY in murine atherosclerosis was examined using mice with T-cell specific ACLY knockout. CD4Cre+Aclyfl/fl mice had reductions in T-bet+ Tregs and increased plaque stability compared to CD4Cre-Aclyfl/fl mice, indicating a pro-atherogenic role for T-cell ACLY. Overall, our findings support a role for T-cell ACLY in atherosclerosis. Funding Sources Supported by T32AI138932; NIAID R01AI153167; NIH R21AI176219; VA Merit Grant I01BX002968 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)