PKCtheta selectively controls the adhesion-stimulating molecule Rap1.

The antigen-specific interaction of a T cell with an antigen-presenting cell (APC) results in the formation of an immunological synapse (IS) between the membranes of the two cells. beta2-integrins on the T cell, namely LFA-1 and its counter ligand, namely ICAM-1 on the APC, critically stabilize this intercellular interaction. The small GTPase Rap1 controls T cell adhesion through modulating the affinity and/or spatial organization of LFA-1; however, the upstream regulatory components triggered by the T cell receptor have not been resolved. In the present study, we identified a previously unknown function of a PKC : RapGEF2 complex in LFA-1 avidity regulation in T lymphocytes. After T cell activation, the direct phosphorylation of RapGEF2 at Ser-960 by PKC regulates Rap1 activation as well as LFA-1 adhesiveness to ICAM-1. In OT-II TCR-transgenic CD4(+) T cells, clustering of LFA-1 after antigen-activation was impaired in the absence of PKC. These data define that, among other pathways acting on LFA-1 regulation, PKC and its effector RapGEF2 are critical factors in T cell receptor signaling to Rap1. Taken together, PKC sets the threshold for T cell activation by positively regulating both the cytokine responses and the adhesive capacities of T lymphocytes.