Disc Large Homolog 1 is critical for early microcluster formation and activation in human T cells

T cell activation by antigen involves multiple sequential steps, including TCR-microcluster (MC) formation, immunological synapse formation and phosphorylation of mediators downstream of the TCR. The adaptor protein Disc Large Homolog 1 (DLG1) is known to regulate proximal TCR signaling and, in turn, T cell activation, acting as a molecular chaperone that organizes specific kinases downstream of antigen recognition. Here, we report using knockdown and knockout studies in human T cells that DLG1 functions even earlier to regulate T cell activation by promoting TCR-MC formation. Moreover, we found that DLG1 can act as a bridge between the TCR-{zeta} chain and ZAP70 while inhibiting binding of the phosphatase SHP1 to TCR-{zeta}. Together, these effects drive dysregulation of T cell activation in DLG1-deficient T cells.