Regulation of NK cell trafficking by CD81

Abstract

NK cells, a heterogeneous sub-population of lymphocytes, are critically involved in the regulation of both innate and adaptive immune responses in humans. Besides their participation in the control of tumors and viral infections, they also regulate inflammatory processes, mediating both beneficial and detrimental effects. To effectively fulfil their role in immune surveillance, proper trafficking of NK cells is essential. However, the mechanisms and factors governing NK cell recruitment are only poorly dissected. Here, we describe the functional role of tetraspanins, a family of evolutionary conserved cellsurface proteins, in modulating migration and transmigration of human NK cells. We demonstrate expression of various tetraspanins on NK cells. Furthermore, we show that stimulation of the NK cell-expressed tetraspanin CD81 induces phosphorylation of ezrin/ radixin/moesin proteins and leads to NK cell polarization thereby facilitating NK cell migration toward various chemokines/cytokines. Finally, we provide evidence for a role of CD81 in promoting adhesion of NK cells to components of the extracellular matrix, a prerequisite for extravasation of lymphocytes in inflamed tissues. Thus, our data suggest that the tetraspanin CD81 is importantly involved in the regulation of NK cell recruitment.Key words: Adhesion . Cell migration . Cell trafficking . Chemokines . NK cells Supporting Information available onlineIntroduction NK cells, a heterogeneous sub-population of lymphocytes, are a central part of the innate immune system. Due to their ability to rapidly attack target cells without prior immunization, NK cells can control infection by viruses, and many studies indicate a role for NK cells in the control of tumor development in mice [1]. Moreover, NK cells are also involved in the regulation of adaptive immune responses via secretion of pro-inflammatory cytokines [2] and modulation of interactions between APC and T cells. In addition, NK cells can act as APC themselves [3].In contrast to their beneficial role in the control of malignancies and invading pathogens, NK cells have been shown to also act as mediators of innate immunopathology (reviewed in [1]). Thus, NK cells do not only participate in the control of tumors and viral infections, but also regulate inflammatory processes and influence subsequent adaptive immune responses, mediating both beneficial and detrimental effects.To fulfil their role in immune surveillance, proper trafficking of NK cells is essential. In general, NK cells are found widely Eur. J. Immunol. 2009. 39: 3447-3458 DOI 10.1002 Innate immunity 3447 distributed in the body. Upon inflammation, NK cells are rapidly recruited into various organs such as the lung, liver, or central nervous system following gradients of chemokines and lysolipids, and can then extravasate into the parenchyma or body cavities, resulting in marked NK cell accumulation within inflamed tissues/organs. This requires that NK cells interact with the vessel wall under flow conditions, arrest, and transmigrate. All th...

Tetraspanins in Cell Migration

“…131 Natural killer cells show substantial expression of CD81, CD63, and CD151 on their cell surface, and stimulation of CD81 with an immobilized antibody induces phosphorylation of ezrin/radixin/moesin proteins, facilitating natural killer cell migration toward various chemokines. 132 In endothelial cells, tetraspanins associate with cell adhesion proteins such as ICAM-1 and VCAM-1 at cell-cell contact sites with transmigrating leukocytes, and endothelial CD9/ CD151 silencing prevents lymphocyte transendothelial migration. 94,133 Additionally, CD63-null HUVECs fail to recruit leukocytes, and CD63-null mice show reduced leukocyte rolling, recruitment, and extravasation, a phenotype similar to that associated with loss of P-selectin.…”

CD81 is essential for the formation of membrane protrusions and regulates Rac1-activation in adhesion-dependent immune cell migration

“…They initiate activation of the small GTPases of the Rho family (Rac1, RhoA, and Cdc42) that play critical roles in signal transduction and actin cytoskeletal reorganization during lamellipodia formation. 23 Notwithstanding previous reports on the molecular functions of tetraspanin proteins in regulating cell motility, 24,25 our understanding of the specific role of CD81 in immune cell migration has remained fragmentary. We show here that CD81 is essential for dendritic cell (DC) migration on 2-dimensional surfaces but not for their chemotaxis in 3-dimensional collagen.…”

Cross-talk between Tetraspanin CD9 and Transmembrane Adaptor Protein Non-T Cell Activation Linker (NTAL) in Mast Cell Activation and Chemotaxis

“…Inhibitory Effect of Anti-CD9 on Ag-mediated ChemotaxisPrevious studies showed that tetraspanins are involved in regulation of chemotaxis in several cell types, including mast cells (48,49). In further experiments we therefore tested the effect of the 2H9 anti-CD9 mAb on chemotaxis driven by Ag.…”