The Role Of Tespa1in T Cell Development And Mast Cell Activation

Signaling via the T cell antigen receptor (TCR) during the CD4+CD8+double-positive developmental stage determines thymocyte selection and lineage commitment. Here we describe a previously uncharacterized T cell-expressed protein, Tespal, with critical functions during the positive selection of thymocytes. We found that Tespal-/-mice had fewer mature thymic CD4+and CD8+T cells, indicating impaired thymocyte development. Further studies revealed that Tespal associated with the TCR signaling components PLC-yl and Grb2. Tespal deficiency also resulted in attenuated TCR signaling, as reflected by defective activation of the Erk-AP-1and Ca2+-NFAT pathways. Our findings thus demonstrate that Tespal is a component of the TCR signalosome and is essential for T cell selection and maturation through the regulation of TCR signaling during T cell development.Mast cell is an important subset of immune cells involved inallergic responses. Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in mast cell degranulation and pro-inflammatory cytokine production, which are key effectors in allergic reactions. Here we show that the activation of mast cells is negatively regulated by the newly identified adaptor protein Tespal. We found that loss of Tespal in mouse mast cells led the cells to be hyperresponsive to the stimulation via FcεRI. Mice lacking Tespal also displayed increased sensitivity to IgE-mediated allergic responses. The dysregulated signaling in Tespal-/-mast cells is associated with increased activation of "Grb2-PLC-yl-SLP-76" signaling within LAT signalosome vesus NTAL signalosome. Collectively, our findings reveal that Tespal functions as a orchestrator in mast cell activation by tuning the balance of LAT and NTAL signolosomes assembly.