Novel regulation of LAT-mediated T cell signaling by DNA-PKcs 2613

Abstract Description The allogeneic T cell response contributes significantly to kidney transplant rejection. Despite conventional therapies, approximately one-third of patients fail treatment, leading to poor long-term graft survival. Identifying targetable proteins that regulate the T cell response to alloantigens is crucial for developing therapies to control T cell-mediated rejection (TCMR). We have shown DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is critical for T cell function as DNA-PKcs inhibitors attenuate cytotoxic T cell response to alloantigen resulting in reduced rejection and extended survival of mouse skin grafts emphasizing promise of DNA-PKcs inhibitors as immunotherapy for TCMR. In this study, we aim to characterize the mechanistic role of DNA-PKcs in T cell signaling. We discovered DNA-PKcs is activated by TCR stimulation and phosphorylates the integral T cell signaling scaffold protein, Linker for Activation of T cells (LAT) at serines 224 and 241. Mutation of these serines prevents phosphorylation of LAT at known tyrosine sites altering downstream binding of signaling proteins to LAT and disrupting cytokine production without affecting T cell proliferation. Deletion of DNA-PKcs in mature CD8+ T cells results in dysfunctional T cells unable to control tumor growth or reject allogeneic skin grafts. These results show a critical role of DNA-PKcs in the antigenic response supporting future investigations into DNA-PKcs regulation of T cell signaling to treat TCMR. Funding Sources T32GN150536-02 R21AI173759-02 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)