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

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.