Psoriasis is a chronic inflammatory skin disease associated with a T helper 17 (Th17) response, yet it has proved challenging to identify relevant peptide-based T cell antigens. Langerhans cells show a differential migration phenotype in psoriatic lesions and express constitutively high levels of CD1a, which presents lipid antigens to T cells. In addition, phospholipase A2 (PLA2) is highly expressed in psoriatic lesions and is known to generate neolipid skin antigens for recognition by CD1a-reactive T cells. Here we observed expression of a cytosolic PLA2 (PLA2G4D) in mast cells in psoriatic lesions but not in healthy skin, but unexpectedly also found the PLA2G4D activity to be extracellular. This could be explained by IFN-α-induced mast cell release of exosomes, which transferred cytosolic PLA2 activity to neighbouring CD1a-expressing cells. This led to the generation of neolipid antigens and subsequent recognition by lipid specific CD1a-reactive T cells inducing production of IL-22 and IL-17. Circulating and skin-resident T cells from patients with psoriasis showed elevated PLA2G4D responsiveness compared to healthy controls. Overall these data present an alternative model of psoriasis pathogenesis in which unconventional lipid-specific CD1a-reactive T cells contribute to psoriatic inflammation. The findings suggest that PLA2 inhibition may have therapeutic potential for psoriasis.</p
