033 Cytotoxic T lymphocytes induce keratinocyte PANoptosis via TNF-α in a murine GVHD-like model

Cytotoxic T lymphocyte (CTL)-induced programmed cell deaths, including apoptosis and necroptosis, occur in skin diseases such as graft versus host disease (GVHD) severe drug eruptions. It has been reported that Fas-FasL, perforin, granzyme B induce these tumor necrosis factor-α (TNF-α) signaling is involved necroptosis. However, the molecular mechanisms of TNF-α deaths induced by CTLs have yet to be fully understood. Recently, a novel death pathway, PANoptosis, integrates all pyroptosis, apoptosis, necroptosis proposed, while its involvement GVHD still unknown. To address this gap knowledge, we administered inhibitor, etanercept, murine GVHD-like model with Ivl-mOVA mice generated. These transgenic express membrane-bound ovalbumin (mOVA) specifically epidermis under control involucrin (Ivl) promoter. By transfer OVA-specific CD8+T cells from OT-I mice, developed dermatitis day 7, half them died 21. The administration etanercept ameliorated improved survival rate. Flow cytometry annexin V staining detected many apoptotic keratinocytes on 14, were reduced treatment. Interestingly, an z-VAD, failed improve mortality, PANoptosis necrostatin-1 (nec-1), mortality. results indicate keratinocyte are via PANoptosis. interferon-γ trigger synergistically, mRNA levels cytokines increased ear mice. Our study demonstrates TNF-α-mediated controls during CTL-related dermatosis could therapeutic target for PANoptosis-related diseases.