A genetically selective inhibitor reveals a ZAP-70 catalytic-independent function in T(REG) cells

To investigate the role of the kinase zeta-associated protein of 70 kDa (ZAP-70) in T cells, we generated mice expressing a ZAP-70 mutant whose catalytic activity can be selectively blocked by a small molecule inhibitor. Conventional naïve, effector and memory T cells were dependent on ZAP-70 kinase activity for their activation, demonstrating a non-redundant role for ZAP-70 in TCR-induced signals. In contrast, ZAP-70 catalytic activity was not required for activation of the GTPase Rap1 and inside-out signals that promote integrin adhesion. This ZAP-70 kinase-independent pathway is sufficient for regulatory T (T(REG)) cell suppressive activity, which was unperturbed by ZAP-70 catalytic inhibition. Our results implicate ZAP-70 as an attractive therapeutic target.