PLA2G12A-driven extracellular vesicle-lipid signaling amplifies pathogenic T cell responses in inflammatory diseases

Summary Extracellular vesicles (EVs) contribute to intercellular communication, yet how EV-driven lipid signaling is regulated in immune responses remains incompletely understood. Here, we show that genetic deficiency or antibody-mediated neutralization of PLA2G12A, a secreted phospholipase A₂ (sPLA₂) transiently upregulated in activated CD4⁺ T cells, prevents pathogenic Th17 differentiation and associated diseases including psoriasis and arthritis. PLA2G12A acts on T cell-derived EVs to produce lysophospholipids including the RORγt activator 1-oleoyl-lysophosphatidylethanolamine. Furthermore, these lysophospholipids are converted by autotaxin to lysophosphatidic acid, which amplifies Th17 differentiation via the LPA₂ receptor. Moreover, PLA2G12A promotes the secretion and uptake of EVs by Th17 cells and alters their cargo contents. Defective Th17 differentiation by PLA2G12A deficiency is restored by supplementation with PLA2G12A-modified EVs. These results provide a rationale for the sPLA₂-EV-lysophospholipid axis as a general mode of sPLA₂ action and suggest that targeting PLA2G12A may be useful for the treatment of Th17-related or possibly other inflammatory diseases.