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Abstract
Natural killer (NK) cells play an important role in first-line defense against tumor and virus-infected cells. The activity of NK cells is tightly regulated by a repertoire of cell surface expressed inhibitory and activating receptors. NKp46 is a major NK cell-activating receptor that is involved in the elimination of target cells. NK cells form different types of synapses that result in distinct functional outcomes: cytotoxic, inhibitory, and regulatory. Recent studies revealed that complex integration of NK receptor signaling controls cytoskeletal rearrangement and other immune synapse-related events. However, the distinct nature by which NKp46 participates in NK immunological synapse formation and function remains unknown. In this study, we determined that NKp46 forms microclusters structures at the immune synapse between NK cells and target cells. Over-expression of human NKp46 is correlated with increased accumulation of F-actin mesh at the immune synapse. Concordantly, knock-down of NKp46 in primary human NK cells decreased recruitment of F-actin to the synapse. Live cell imaging experiments showed a linear correlation between NKp46 expression and lytic granules polarization to the immune synapse. Taken together, our data suggest that NKp46 signaling directly regulates the NK lytic immune synapse from early formation to late function.
Highlights
Natural killer (NK) cells are granular lymphocytes that were initially recognized for their capacity to efficiently eliminate tumor cells without prior sensitization [1, 2]
Control of NK cell function is mainly regulated by is recognition of Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; HA, hemagglutinin; HS, heparan sulfate; KIRs, killer-cell immunoglobulin-like receptors; MTOC, microtubule-organizing center; natural cytotoxicity receptors group (NCR), natural cytotoxicity receptor; pSMAC, peripheral supra molecular activating cluster; WASp, Wiskott–Aldrich syndrome protein
Measuring the distribution of labeled NKp46 in 24 NK-target cell conjugations indicated that 58 ± 8% of the membrane-associated NKp46 receptor molecules are accumulating at the immune synapse (Figure 1E)
Summary
Natural killer (NK) cells are granular lymphocytes that were initially recognized for their capacity to efficiently eliminate tumor cells without prior sensitization [1, 2]. Viral infections can induce NK cytotoxicity [3]. NK cells compromise 5–15% of peripheral blood lymphocytes [6]. The majority of NK cells (~90%) are CD56dim CD16bright, and can induce a strong cytolytic response, while 10% are CD56bright–CD16null/dim and are capable of rapid cytokine secretion [7]. Control of NK cell function is mainly regulated by is recognition of Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; HA, hemagglutinin; HS, heparan sulfate; KIRs, killer-cell immunoglobulin-like receptors; MTOC, microtubule-organizing center; NCR, natural cytotoxicity receptor; pSMAC, peripheral supra molecular activating cluster; WASp, Wiskott–Aldrich syndrome protein
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