title: Wiskott-Aldrich syndrome protein (WASp) and N-WASp are involved in the regulation of NK-cell migration upon NKG2D activation.
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.
authors.affiliation: Immunology Department, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Serrano-Pertierra
authors.forename: Eva
authors.initials: E
authors.lastname: Cernuda-Morollón
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Larrea
mesh_terms: D002478:Cells, Cultured; D054377:Chemokine CXCL12; D002634:Chemotaxis, Leukocyte; D015536:Down-Regulation; D006801:Humans; D057131:Immune Evasion; D007694:Killer Cells, Natural / Q000502:physiology*; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C527085:KLRK1 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034741:RNA, Small Interfering; D051316:Wiskott-Aldrich Syndrome Protein; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein