Talin is required for LFA-1-induced natural killer cell polarization and cytotoxicity (91.1)

Abstract

Abstract The purpose of this study is to elucidate the role that the cytoskeletal adaptor protein talin1 plays in the function of the integrin leukocyte function associated antigen-1 (LFA-1) in NK cells. It has been proposed that LFA-1 not only mediates adhesion of NK cells to target cells but is also an important activating receptor for NK cell cytotoxicity. Talin is known to act as a link between integrins and the actin cytoskeleton and to regulate ligand-binding function of LFA-1. We generated NK cells in vitro from talin1 knockout (KO) embryonic stem cells, tested the effects of talin deficiency on these NK cells, and found that talin plays a dual role in NK cell cytotoxicity. First, it is required for LFA-1 mediated adhesion to the target cell. Second, it is required for the accumulation of actin and actin polymerization machinery, including vinculin and WASP, following binding of LFA-1 to its ligand ICAM-1.This LFA-1- and talin-dependent actin accumulation is a critical for further steps leading to NK cell cytotoxicity. Although talin-KO NK cells adhere to target cells in the presence of Mn++, they are unable to kill the prototypic NK target YAC-1. Wild-type, but not talin-KO, NK cells polarize cytotoxic granules following engagement of both LFA-1 and the activating receptor NKG2D. These data show that LFA-1 mediated actin accumulation precedes and is required for subsequent signalling that leads to cytotoxicity. This work is supported by a grant from the Canadian Institutes of Health Research (CIHR).