Cdc42/Rac function in NK cells and CTLs is variable and governed by spatiotemporal patterning of Cdc42/Rac

Abstract

Natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) are central immune effectors. They activate in a cellular interaction with target cells, leading to target cell lysis and IFN? secretion. These effector functions require effective cellular polarization. We have therefore studied roles of Cdc42 and Rac, two general regulators of cellular polarization, in primary NK cells and CTLs. NK cells were primed with IL‐2, IL‐12/IL‐18, or IL‐15, reflecting different physiological and therapeutically used activation conditions. We expected that Cdc42/Rac by promoting cellular polarization would support effector functions. Surprisingly however, functions of Cdc42/Rac varied dramatically between the different cell types and activation conditions. When we determined the spatiotemporal patterns of Cdc42/Rac activity in NK cell/CTL – target cell interactions, we intriguingly found that Cdc42/Rac could only support effector functions when enriched at the center of the effector/target cell interface. Our data thus establish that Cdc42/Rac function in NK cells and CTLs is not only governed by the activation of these proteins but, as importantly, by the location of this activation.Supported by the NIH