Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a

• DOI: 10.1084/jem.20160258
• Publication Date: 2016-09-26T14:13:30Z
• Authors: Ka Lun Cheung; Rachael Jarrett; Sumithra Subramaniam; Maryam Salimi; Danuta Gutowska-O...; Yi-Ling Chen; Clare Hardman; Luzheng Xue; Vincenzo Cerundolo; Graham Ogg
• Keywords: 0301 basic medicine; Antigen Presentation; Group IV Phospholipases A2; T-Lymphocytes; Exosomes; Lymphocyte Activation; Lipids; Clathrin; Endocytosis; 3. Good health; Antigens, CD1; Cohort Studies; 03 medical and health sciences; Cytosol; Case-Control Studies; Humans; Psoriasis; Mast Cells; K562 Cells; Research Articles; Skin

Psoriasis is a chronic inflammatory skin disease associated with a T helper 17 response. Yet, it has proved challenging to identify relevant peptide-based T cell antigens. Antigen-presenting 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. In this study, we observed expression of a cytoplasmic PLA2 (PLA2G4D) in psoriatic mast cells but, unexpectedly, also found PLA2G4D activity to be extracellular. This was explained by IFN-α–induced mast cell release of exosomes, which transferred cytoplasmic PLA2 activity to neighboring 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-17A. Circulating and skin-derived T cells from patients with psoriasis showed elevated PLA2G4D responsiveness compared with healthy controls. Overall, these data present an alternative model of psoriasis pathogenesis in which lipid-specific CD1a-reactive T cells contribute to psoriatic inflammation. The findings suggest that PLA2 inhibition or CD1a blockade may have therapeutic potential for psoriasis.