STAP-1 is a novel adaptor protein to promote TCR-mediated T cell activation and autoimmune inflammation 2081

Abstract Description Signal-Transducing Adaptor Protein-1 (STAP-1) is an adaptor protein that contains pleckstrin and Src homology-2 domains, specifically expressed in immune cells such as T cells. Therefore, we hypothesized that STAP-1 plays some roles in T cell functions and analyzed the role of STAP-1 in human/murine T cells. STAP-1 deficiency downregulated T cell activation, determined by impaired TCR-mediated phosphorylation of downstream molecules, IL-2 production and cell proliferation both in human cells and murine CD4+ T cells. In molecular analysis, we found that STAP-1 plays a critical role for T cell activation by interacting with LCK and PLC-γ1 as a scaffold upon TCR engagement. Furthermore, STAP-1 KO mice exhibited lower pathogenesis in experimental autoimmune encephalomyelitis (EAE) by downregulating the activation of Th1 and Th17, as well as infiltration of these cells into CNS. Conversely, STAP-1 overexpression promotes T cell activation in vitro, as well as pathogenesis of EAE in vivo. Taken together, we hypothesized that pharmacological inhibition of STAP-1-LCK binding can be a new therapeutic target of T cell-mediated autoimmune diseases. Therefore, we generated STAP-1-derived peptide which inhibits STAP-1-LCK binding. STAP-1 inhibitor successfully suppressed TCR-mediated T cell activation both in human and murine T cells. Our findings indicate that STAP-1 is a key regulator of T cells and is a promising target of T cell-mediated autoimmune and inflammatory diseases. Funding Sources Supported by Japan Society for the Promotion of Science Grants- in-Aid for Scientific Research 19H03364,16K09872,21K08451 and Japan Agency for Medical Research and Development Grant 23ym0126801j0002 through the Translational Research Program, Strategic Promotion for Practical Application of Innovative Medical Technology. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)