Abstract
NKG2D is a transmembrane receptor mainly expressed on CD8(+) T cells and NK cells. Engagement of NKG2D with its ligands can trigger a cytotoxic response. It has been shown that tumor cells deliver soluble NKG2D ligands as a mechanism of immune evasion through the downregulation of surface-expressed NKG2D. These ligands may be also secreted in microvesicles and regulate NK-cell function, but the existence of alternative mechanisms has not been explored. In this study, we describe that NKG2D activation inhibits NK-cell chemotaxis toward a CXCL12 gradient. Costimulation of the inhibitory receptor NKG2A rescues NK-cell migration rates. Thus, the balance of NKG2D/NKG2A activation may determine the migratory ability of NK cells. Furthermore, our data indicated that NKG2D cross-linking induces the activation of the Rho GTPases Rac1 and Cdc42, while RhoA activity is decreased. Pharmacological inhibition of the Cdc42 effectors Wiskott-Aldrich syndrome protein (WASp)/N-WASp, and the reduction of their levels using RNA interference partially abolished NKG2D-mediated impairment of cell migration, suggesting a pivotal role of Cdc42 in the regulation of NK-cell migration by NKG2D activation. Therefore, our results provide a new mechanism that may contribute to the immune response or evasion in tumors.