Abstract
Natural killer (NK) cells are lymphocytes of the innate immune system that are critical in host defense. They are best known for their ability to mediate cytotoxicity, which involves a coordinated series of events resulting in the directed secretion of lytic granules onto a target cell. This process requires the formation of an immunological synapse in NK cells. The NK cell immunological synapse involves the reorganization of the actin cytoskeleton and clustering of certain cell surface receptors in the NK cell at the interface with the target cell. The lytic NK cell immunological synapse, specialized for mediating cytotoxicity, is further distinguished by the polarization of lytic granules, which are then secreted through this region onto the target cell. These events unfold in a definitive sequence and lead to critical checkpoints that provide regulatory control at specific stages in the formation of the NK cell lytic synapse.
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Badour, K., Zhang, J., Shi, F., McGavin, M.K., Rampersad, V., Hardy, L.A., Field, D. and Siminovitch, K.A. (2003) The Wiskott-Aldrich syndrome protein acts downstream of CD2 and the CD2AP and PSTPIP1 adaptors to promote formation of the immunological synapse. Immunity 18, 141–154.
Barda-Saad, M., Braiman, A., Titerence, R., Bunnell, S.C., Barr, V.A. and Samelson, L.E. (2005) Dynamic molecular interactions linking the T cell antigen receptor to the actin cytoskeleton. Nat. Immunol. 6, 80–89.
Biron, C.A., Nguyen, K.B., Pien, G.C., Cousens, L.P. and Salazar-Mather, T.P. (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220.
Blom, W.M., de Bont, H.J., Meijerman, I., Kuppen, P.J., van Der Meulen, H., Mulder, G.J. and Nagelkerke, J.F. (2001) Remodeling of the actin cytoskeleton of target hepatocytes and NK cells during induction of apoptosis. Cell. Motil. Cytoskeleton 49, 78–92.
Bryceson, Y.T., March, M.E., Barber, D.F., Ljunggren, H.G. and Long, E.O. (2005) Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. J. Exp. Med. 202, 1001–1012.
Burkhardt, J.K., McIlvain, J.M., Jr., Sheetz, M.P. and Argon, Y. (1993) Lytic granules from cytotoxic T cells exhibit kinesin-dependent motility on microtubules in vitro. J. Cell. Sci. 104, 151–162.
Carpen, O., Virtanen, I., Lehto, V.P. and Saksela, E. (1983) Polarization of NK cell cytoskeleton upon conjugation with sensitive target cells. J. Immunol. 131, 2695–2698.
Clark, R.H., Stinchcombe, J.C., Day, A., Blott, E., Booth, S., Bossi, G., Hamblin, T., Davies, E.G. and Griffiths, G.M. (2003) Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse. Nat. Immunol. 4, 1111–1120.
Comans-Bitter, W.M., de Groot, R., van den Beemd, R., Neijens, H.J., Hop, W.C., Groeneveld, K., Hooijkaas, H. and van Dongen, J.J. (1997) Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations. J. Pediatr. 130, 388–393.
Davis, D.M., Chiu, I., Fassett, M., Cohen, G.B., Mandelboim, O. and Strominger, J.L. (1999) The human natural killer cell immune synapse. Proc. Natl. Acad. Sci. USA 96, 15062–15067.
Davis, D.M. and Dustin, M.L. (2004) What is the importance of the immunological synapse? Trends Immunol. 25, 323–327.
Desai, A. and Mitchison, T.J. (1997) Microtubule polymerization dynamics. Annu. Rev. Cell Dev. Biol. 13, 83–117.
Fehniger, T.A., Cooper, M.A. and Caligiuri, M.A. (2002) Interleukin-2 and interleukin-15: immunotherapy for cancer. Cytokine Growth Factor Rev. 13, 169–183.
Feldmann, J., Callebaut, I., Raposo, G., Certain, S., Bacq, D., Dumont, C., Lambert, N., Ouachee-Chardin, M., Chedeville, G. and Tamary, H. (2003) Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115, 461–473.
Freiberg, B.A., Kupfer, H., Maslanik, W., Delli, J., Kappler, J., Zaller, D.M. and Kupfer, A. (2002) Staging and resetting T cell activation in SMACs. Nat. Immunol. 3, 911–917.
Goley, E.D. and Welch, M.D. (2006) The ARP2/3 complex: an actin nucleator comes of age. Nat. Rev. Mol. Cell Biol. 7, 713–726.
Graham, D.B., Cella, M., Giurisato, E., Fujikawa, K., Miletic, A.V., Kloeppel, T., Brim, K., Takai, T., Shaw, A.S., Colonna, M. and Swat, W. (2006) Vav1 controls DAP10-mediated natural cytotoxicity by regulating actin and microtubule dynamics. J. Immunol. 177, 2349–2355.
Grakoui, A., Bromley, S.K., Sumen, C., Davis, M.M., Shaw, A.S., Allen, P.M. and Dustin, M.L. (1999) The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221–227.
Ito, M., Tanabe, F., Sato, A., Ishida, E., Takami, Y. and Shigeta, S. (1989) Inhibition of natural killer cell-mediated cytotoxicity by ML-9, a selective inhibitor of myosin light chain kinase. Int. J. Immunopharmacol. 11, 185–190.
Katz, P., Zaytoun, A.M. and Lee, J.H., Jr. (1982) Mechanisms of human cell-mediated cytotoxicity. III. Dependence of natural killing on microtubule and microfilament integrity. J. Immunol. 129, 2816–2825.
Krummel, M.F., Sjaastad, M.D., Wulfing, C. and Davis, M.M. (2000) Differential clustering of CD4 and CD3zeta during T cell recognition. Science 289, 1349–1352.
Kuhn, J.R. and Poenie, M. (2002). Dynamic polarization of the microtubule cytoskeleton during CTL-mediated killing. Immunity 16, 111–121.
Kupfer, A., Dennert, G. and Singer, S.J. (1983) Polarization of the Golgi apparatus and the microtubule-organizing center within cloned natural killer cells bound to their targets. Proc Natl. Acad. Sci. USA 80, 7224–7228.
Lanier, L.L. (2005) NK cell recognition. Annu. Rev. Immunol. 23, 225–274.
Lavie, G., Leib, Z. and Servadio, C. (1985) The mechanism of human NK cell-mediated cytotoxicity. Mode of action of surface-associated proteases in the early stages of the lytic reaction. J. Immunol. 135, 1470–1476.
Lee, K.H., Dinner, A.R., Tu, C., Campi, G., Raychaudhuri, S., Varma, R., Sims, T.N., Burack, W.R., Wu, H., Wang, J. and Shaw, A.S. (2003) The immunological synapse balances T cell receptor signaling and degradation. Science 302, 1218–1222.
Lee, K.H., Holdorf, A.D., Dustin, M.L., Chan, A.C., Allen, P.M. and Shaw, A.S. (2002) T cell receptor signaling precedes immunological synapse formation. Science 295, 1539–1542.
Lou, Z., Billadeau, D.D., Savoy, D.N., Schoon, R.A. and Leibson, P.J. (2001) A role for a RhoA/ROCK/LIM-kinase pathway in the regulation of cytotoxic lymphocytes. J. Immunol. 167, 5749–5757.
Masilamani, M., Nguyen, C., Kabat, J., Borrego, F. and Coligan, J.E. (2006) CD94/NKG2A inhibits NK cell activation by disrupting the actin network at the immunological synapse. J. Immunol. 177, 3590–3596.
McCann, F.E., Vanherberghen, B., Eleme, K., Carlin, L.M., Newsam, R.J., Goulding, D. and Davis, D.M. (2003) The size of the synaptic cleft and distinct distributions of filamentous actin, ezrin, CD43, and CD45 at activating and inhibitory human NK cell immune synapses. J. Immunol. 170, 2862–2870.
Miller, J.S. (2001) The biology of natural killer cells in cancer, infection, and pregnancy. Exp. Hematol. 29, 1157–1168.
Moretta, L., Bottino, C., Pende, D., Mingari, M.C., Biassoni, R. and Moretta, A. (2002) Human natural killer cells: their origin, receptors and function. Eur. J. Immunol. 32, 1205–1211.
Moretta, L. and Moretta, A. (2004) Killer immunoglobulin-like receptors. Curr. Opin. Immunol. 16, 626–633.
Mossman, K.D., Campi, G., Groves, J.T. and Dustin, M.L. (2005) Altered TCR signaling from geometrically repatterned immunological synapses. Science 310, 1191–1193.
Orange, J.S. (2002) Human natural killer cell deficiencies and susceptibility to infection. Microbes Infect. 4, 1545–1558.
Orange, J.S. (2006) Human natural killer cell deficiencies. Curr. Opin. Allergy Clin. Immunol. 6, 399–409.
Orange, J.S. and Ballas, Z.K. (2006) Natural killer cells in human health and disease. Clin. Immunol. 118, 1–10.
Orange, J.S., Fassett, M.S., Koopman, L.A., Boyson, J.E. and Strominger, J.L. (2002a) Viral evasion of natural killer cells. Nat. Immunol. 3, 1006–1012.
Orange, J.S., Harris, K.E., Andzelm, M.M., Valter, M.M., Geha, R.S. and Strominger, J.L. (2003) The mature activating natural killer cell immunologic synapse is formed in distinct stages. Proc. Natl. Acad. Sci. USA 100, 14151–14156.
Orange, J.S., Ramesh, N., Remold-O’Donnell, E., Sasahara, Y., Koopman, L., Byrne, M., Bonilla, F.A., Rosen, F.S., Geha, R.S. and Strominger, J.L. (2002b) Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc. Natl. Acad. Sci. USA 99, 11351–11356.
Orange, J.S., Stone, K.D., Turvey, S.E. and Krzewski, K. (2004) The Wiskott-Aldrich syndrome. Cell. Mol. Life Sci. 61, 2361–2385.
Pende, D., Parolini, S., Pessino, A., Sivori, S., Augugliaro, R., Morelli, L., Marcenaro, E., Accame, L., Malaspina, A., Biassoni, R., Bottino, C., Moretta, L. and Moretta, A. (1999) Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J. Exp. Med. 190, 1505–1516.
Pessino, A., Sivori, S., Bottino, C., Malaspina, A., Morelli, L., Moretta, L., Biassoni, R. and Moretta, A. (1998) Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. J. Exp. Med. 188, 953–960.
Poggi, A., Panzeri, M.C., Moretta, L. and Zocchi, M.R. (1996) CD31-triggered rearrangement of the actin cytoskeleton in human natural killer cells. Eur. J. Immunol. 26, 817–824.
Pollard, T.D. and Borisy, G.G. (2003) Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453–465.
Purtic, B., Pitcher, L.A., van Oers, N.S. and Wulfing, C. (2005) T cell receptor (TCR) clustering in the immunological synapse integrates TCR and costimulatory signaling in selected T cells. Proc. Natl. Acad. Sci. USA 102, 2904–2909.
Quan, P.C., Ishizaka, T. and Bloom, B.R. (1982) Studies on the mechanism of NK cell lysis. J. Immunol. 128, 1786–1791.
Radosevic, K., van Leeuwen, A.M., Segers-Nolten, I.M., Figdor, C.G., de Grooth, B. and Greve, J. (1995) Occurrence and a possible mechanism of penetration of natural killer cells into K562 target cells during the cytotoxic interaction. Cytometry 20, 273–280.
Sancho, D., Nieto, M., Llano, M., Rodriguez-Fernandez, J.L., Tejedor, R., Avraham, S., Cabanas, C., Lopez-Botet, M. and Sanchez-Madrid, F. (2000) The tyrosine kinase PYK-2/RAFTK regulates natural killer (NK) cell cytotoxic response, and is translocated and activated upon specific target cell recognition and killing. J. Cell. Biol. 149, 1249–1262.
Smith, K.A. (2001) Low-dose daily interleukin-2 immunotherapy: accelerating immune restoration and expanding HIV-specific T cell immunity without toxicity. Aids 15, S28–35.
Stebbins, C.C., Watzl, C., Billadeau, D.D., Leibson, P.J., Burshtyn, D.N. and Long, E.O. (2003) Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity. Mol. Cell. Biol. 23, 6291–6299.
Stinchcombe, J.C., Majorovits, E., Bossi, G., Fuller, S. and Griffiths, G.M. (2006) Centrosome polarization delivers secretory granules to the immunological synapse. Nature 443, 462–465.
Tay, C.H., Szomolanyi-Tsuda, E. and Welsh, R.M. (1998) Control of infections by NK cells. Curr .Top. Microbiol. Immunol. 230, 193–220.
Trambas, C.M. and Griffiths, G. (2003) Delivering the kiss of death. Nat. Immunol 4, 399–403.
Vicente-Manzanares, M. and Sanchez-Madrid, F. (2004) Role of the cytoskeleton during leukocyte responses. Nat. Rev. Immunol. 4, 110–122.
Vyas, Y.M., Maniar, H., Lyddane, C.E., Sadelain, M. and Dupont, B. (2004) Ligand binding to inhibitory killer cell Ig-like receptors induce colocalization with Src homology domain 2-containing protein tyrosine phosphatase 1 and interruption of ongoing activation signals. J. Immunol. 173, 1571–1578.
Vyas, Y.M., Mehta, K.M., Morgan, M., Maniar, H., Butros, L., Jung, S., Burkhardt, J.K. and Dupont, B. (2001) Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions. J. Immunol. 167, 4358–4367.
Wu, J., Song, Y., Bakker, A.B., Bauer, S., Spies, T., Lanier, L.L. and Phillips, J.H. (1999) An activating immunoreceptor complex formed by NKG2D and DAP10. Science 285, 730–732.
Wulfing, C. and Davis, M.M. (1998) A receptor/cytoskeletal movement triggered by costimulation during T cell activation. Science 282, 2266–2269.
Wulfing, C., Purtic, B., Klem, J. and Schatzle, J.D. (2003) Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing. Proc. Natl. Acad. Sci. USA 100, 7767–7772.
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Orange, J.S. (2007). The Lytic NK Cell Immunological Synapse and Sequential Steps in Its Formation. In: Shurin, M.R., Smolkin, Y.S. (eds) Immune-Mediated Diseases. Advances in Experimental Medicine and Biology, vol 601. Springer, New York, NY. https://doi.org/10.1007/978-0-387-72005-0_23
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DOI: https://doi.org/10.1007/978-0-387-72005-0_23
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