A Dual Role for Talin in NK Cell Cytotoxicity: Activation of LFA-1-Mediated Cell Adhesion and Polarization of NK Cells

Abstract

LFA-1 is critical for NK cell cytotoxicity because it mediates adhesion of NK cells to target cells. Talin is thought to associate with the cytoplasmic tail of LFA-1 and activates its ligand-binding function. In this study, we report that talin is also required for LFA-1-mediated outside-in signaling leading to NK cell polarization. NK cells generated from talin1-deficient murine embryonic stem cells are defective in LFA-1-mediated adhesion. Although exogenously added manganese activates LFA-1 on talin-deficient NK cells and induces conjugate formation with target cells, their LFA-1-dependent cytotoxicity is impaired. Binding of ICAM-1-coated beads to wild-type NK cells induces reorganization of the actin cytoskeleton and coligation of the activating receptor NKG2D induces polarization of cytotoxic granules, whereas talin1-deficient NK cells fail to polarize with or without NKG2D coligation. Thus, talin1 plays a dual role in NK cell cytotoxicity, first by activation of LFA-1-mediated adhesion and then via LFA-1-induced NK cell polarization.

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“…Each of these reagents has been shown to be biologically active in our hands in several different systems (20,(22)(23)(24)(25)(26), and V. Ho, M. Hamilton, and G. Krystal, unpublished results). We first determined whether cytokines that have been reported to alter Mf phenotype (i.e., IL-4, IL-13) (12) or restrict T cell proliferation (i.e., IL-10, TGF-b) (27) were involved.…”

Elucidation of the integrin LFA-1–mediated signaling pathway of actin polarization in natural killer cells

“…6 Talin-KO mice are not viable. 21 Therefore, we generated NK cells in vitro from talin-KO and WT ES cells as in our previous study 6 .…”

“…Similarly, talin-KO ES-derived NK cells bound ICAM-1 after treatment with Mn ϩϩ as previously shown. 6 Upon binding of ICAM-1-coated beads, talin ( Figure 3A) and Arp2/3 ( Figure 3B) accumulated at the contact site in all 3 types of WASP-KO NK cells. Vinculin ( Figure 3C) also accumulated at the contact site in ex vivo and IL-15-activated WASP-KO NK cells, but unexpectedly no significant accumulation of vinculin was seen in IL-2-activated WASP-KO NK cells.…”

“…4,5 We have shown that binding of LFA-1 on NK cells to ICAM-1, in the absence of other activation signals, results in localized actin accumulation and that the cytoskeletal adaptor protein talin is required for this process. 6 However, the precise mechanism by which LFA-1 ligation results in the reorganization of the actin cytoskeleton and how talin plays a critical role in the process remains unclear.Talin is a large adaptor protein with a 50-kDa head and a 200-kDa rod domain. Talin head contains a FERM domain that binds the ␤ subunit of integrin cytoplasmic tails and activates integrin functions.…”

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“…LFA-1 activation in NK cells also resulted in Pyk2 autophosphorylation and talin enrichment at the site of contact between the NK cell and the target cell (Fig. 4D) (94). Moreover, granule polarization and cytotoxicity require Pyk2 activation (95).…”