310 Unopposed IL-36 activity promotes clonal CD4+ T-cell responses with IL-17A production in generalized pustular psoriasis

Abstract

Generalized pustular psoriasis (GPP) is the most severe psoriasis variant. Proinflammatory mutations in the IL-36 antagonist, IL36RN, in CARD14 or AP1S3 indicate autoinflammatory aetiology. Though T-cell involvement in GPP is obvious from clinical observations and experimental animal models, the mode of T-cell contributions remains elusive. Here we demonstrate that unopposed IL-36 signalling may cooperate with certain HLA-class II-alleles to induce antigen-driven Th17 responses in GPP, which in the absence of exogenous triggers are presumably directed against autoantigens. We analysed IL36RN variants, HLA haplotypes and IL36RN transcriptions in 8 GPP patients. Molecular analysis of T-cell receptor (TCR) rearrangements determined T-cell diversity. [3H]-thymidine or BrdU incorporation, CFSE dilution and Ki-67 staining defined T-cell proliferation. IL-17A production was assessed by in situ or intracellular immunofluorescence staining. We observed that deficits in IL36RN function may result from mutations or decreased IL36RN transcription independent from IL36RN mutations. CD4+ T cells of GPP patients were characterized by strong autoproliferation, highly restricted clonal TCR repertoires and identical T-cell clones in blood and skin lesions, and predominant differentiation into T-helper 17 (Th17) cells. IL-17A production was particular evident for the clonal CD4+ T-cell populations. IL36B substantially enhanced TCR-mediated proliferation of CD4+ T cells in vitro. These alterations were associated with certain HLA-class II alleles, HLA-DQB1*03, HLA-DQB1*05 and HLA-DRB1*14. GPP might therefore represent a disease where autoinflammation promotes CD4+ T-cell mediated autoimmunity in the context of HLA-class II association. Whereas CD8+ T-cell mediated autoimmune response against melanocytes drives psoriasis vulgaris, this study demonstrates that CD4+ T cells substantially contribute to GPP pathogenesis.