Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a.
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 PLA2activity 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 PLA2inhibition or CD1a blockade may have therapeutic potential for psoriasis.
Medical Research Council Human Immunology Unit, National Institute for Health Research Biomedical Research Center, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK.
Ka Lun
0000-0001-6582-1027
KL
Cheung
Medical Research Council Human Immunology Unit, National Institute for Health Research Biomedical Research Center, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK.
Rachael
0000-0002-0572-4425
R
Jarrett
Medical Research Council Human Immunology Unit, National Institute for Health Research Biomedical Research Center, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK.
Sumithra
0000-0003-0573-4380
S
Subramaniam
Medical Research Council Human Immunology Unit, National Institute for Health Research Biomedical Research Center, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK.
Maryam
M
Salimi
Medical Research Council Human Immunology Unit, National Institute for Health Research Biomedical Research Center, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK.
Danuta
0000-0003-4503-2279
D
Gutowska-Owsiak
Medical Research Council Human Immunology Unit, National Institute for Health Research Biomedical Research Center, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK.
Yi-Ling
YL
Chen
Medical Research Council Human Immunology Unit, National Institute for Health Research Biomedical Research Center, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK.
Clare
C
Hardman
Respiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK.
Luzheng
0000-0003-0042-1262
L
Xue
Medical Research Council Human Immunology Unit, National Institute for Health Research Biomedical Research Center, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK.
Vincenzo
0000-0003-0040-3793
V
Cerundolo
Medical Research Council Human Immunology Unit, National Institute for Health Research Biomedical Research Center, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, England, UK graham.ogg@ndm.ox.ac.uk.
Graham
0000-0002-3097-045X
G
Ogg
D017951:Antigen Presentation / Q000276:immunology*; D018949:Antigens, CD1 / Q000378:metabolism*; D016022:Case-Control Studies; D002966:Clathrin / Q000378:metabolism; D015331:Cohort Studies; D003600:Cytosol / Q000378:metabolism; D004705:Endocytosis; D055354:Exosomes / Q000378:metabolism*; D054513:Group IV Phospholipases A2 / Q000276:immunology*; D006801:Humans; D020014:K562 Cells; D008055:Lipids / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008407:Mast Cells / Q000201:enzymology*; D011565:Psoriasis / Q000097:blood / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D012867:Skin / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*
D018949:Antigens, CD1; C419393:CD1a antigen; D002966:Clathrin; D008055:Lipids; D054513:Group IV Phospholipases A2; C516417:PLA2G4D protein, human
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