Signal Transduction During Activation and Inhibition of Natural Killer Cells

Carsten Watzl1, Eric O. Long2

1 Institute for Immunology, University Heidelberg, Heidelberg, Germany, 2 Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland
Publication Name:  Current Protocols in Immunology
Unit Number:  Unit 11.9B
DOI:  10.1002/0471142735.im1109bs90
Online Posting Date:  August, 2010
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Natural killer (NK) cells are important for early immune responses to viral infections and cancer. Upon activation, NK cells secrete cytokines and chemokines, and kill sensitive target cells by releasing the content of cytolytic granules. This unit is focused on the signal transduction pathways that regulate NK cell activities in response to contact with other cells. We will highlight signals regulating NK cell adhesion to target cells and describe the induction of cellular cytotoxicity by the engagement of different NK cell activation receptors. Negative signaling induced by inhibitory receptors opposes NK cell activation and provides an important safeguard from NK cell reactivity toward normal, healthy cells. We will discuss the complex integration of the different signals that occur during interaction of NK cells with target cells. Curr. Protoc. Immunol. 90:11.9B.1‐11.9B.17. © 2010 by John Wiley & Sons, Inc.

Keywords: natural killer cells; signal transduction; cytotoxicity; adhesion

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Table of Contents

  • Introduction
  • Activation Receptors in Natural Cytotoxicity
  • Fcγ Receptor Signaling
  • Signaling by Integrins
  • Key Events in NK Cell Activation
  • Inhibition
  • Conclusion
  • Literature Cited
  • Figures
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Literature Cited

Literature Cited
   Alon, R. and Dustin, M.L. 2007. Force as a facilitator of integrin conformational changes during leukocyte arrest on blood vessels and antigen‐presenting cells. Immunity 26:17‐27.
   Andzelm, M.M., Chen, X., Krzewski, K., Orange, J.S., and Strominger, J.L. 2007. Myosin IIA is required for cytolytic granule exocytosis in human NK cells. J. Exp. Med. 204:2285‐2291.
   Anfossi, N., Andre, P., Guia, S., Falk, C.S., Roetynck, S., Stewart, C.A., Breso, V., Frassati, C., Reviron, D., Middleton, D., Romagne, F., Ugolini, S., and Vivier, E. 2006. Human NK cell education by inhibitory receptors for MHC class I. Immunity 25:331‐342.
   Anikeeva, N., Somersalo, K., Sims, T.N., Thomas, V.K., Dustin, M.L., and Sykulev, Y. 2005. Distinct role of lymphocyte function‐associated antigen‐1 in mediating effective cytolytic activity by cytotoxic T lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 102:6437‐6442.
   Arase, H., Mocarski, E.S., Campbell, A.E., Hill, A.B., and Lanier, L.L. 2002. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296:1323‐1326.
   Arneson, L.N., Brickshawana, A., Segovis, C.M., Schoon, R.A., Dick, C.J., and Leibson, P.J. 2007. Cutting edge: Syntaxin 11 regulates lymphocyte‐mediated secretion and cytotoxicity. J. Immunol. 179:3397‐3401.
   Arnon, T.I., Markel, G., and Mandelboim, O. 2006. Tumor and viral recognition by natural killer cells receptors. Semin. Cancer Biol. 16:348‐358.
   Ashkar, A.A., Di Santo, J.P., and Croy, B.A. 2000. Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J. Exp. Med. 192:259‐269.
   Banerjee, P.P., Pandey, R., Zheng, R., Suhoski, M.M., Monaco‐Shawver, L., and Orange, J.S. 2007. Cdc42‐interacting protein‐4 functionally links actin and microtubule networks at the cytolytic NK cell immunological synapse. J. Exp. Med. 204:2305‐2320.
   Barber, D.F. and Long, E.O. 2003. Coexpression of CD58 or CD48 with intercellular adhesion molecule 1 on target cells enhances adhesion of resting NK cells. J. Immunol. 170:294‐299.
   Barber, D.F., Faure, M., and Long, E.O. 2004. LFA‐1 contributes an early signal for NK cell cytotoxicity. J. Immunol. 173:3653‐3659.
   Bauer, S., Groh, V., Wu, J., Steinle, A., Phillips, J.H., Lanier, L.L., and Spies, T. 1999. Activation of NK cells and T cells by NKG2D, a receptor for stress‐inducible MICA. Science 285:727‐729.
   Bell, G. M., Fargnoli, J., Bolen, J.B., Kish, L., and Imboden, J.B. 1996. The SH3 domain of p56lck binds to proline‐rich sequences in the cytoplasmic domain of CD2. J. Exp. Med. 183:169‐178.
   Benoit, L., Wang, X., Pabst, H.F., Dutz, J., and Tan, R. 2000. Defective NK cell activation in X‐linked lymphoproliferative disease. J. Immunol. 165:3549‐3553.
   Berditchevski, F. 2001. Complexes of tetraspanins with integrins: More than meets the eye. J. Cell Sci. 114:4143‐4151.
   Billadeau, D.D., Brumbaugh, K.M., Dick, C.J., Schoon, R.A., Bustelo, X.R., and Leibson, P.J. 1998. The Vav‐Rac1 pathway in cytotoxic lymphocytes regulates the generation of cell‐mediated killing. J. Exp. Med. 188:549‐559.
   Billadeau, D.D., Upshaw, J.L., Schoon, R.A., Dick, C.J., and Leibson, P.J. 2003. NKG2D‐DAP10 triggers human NK cell‐mediated killing via a Syk‐independent regulatory pathway. Nat. Immunol. 4:557‐564.
   Bloch‐Queyrat, C., Fondaneche, M.C., Chen, R., Yin, L., Relouzat, F., Veillette, A., Fischer, A., and Latour, S. 2005. Regulation of natural cytotoxicity by the adaptor SAP and the Src‐related kinase Fyn. J. Exp. Med. 202:181‐192.
   Bottino, C., Augugliaro, R., Castriconi, R., Nanni, M., Biassoni, R., Moretta, L., and Moretta, A. 2000. Analysis of the molecular mechanism involved in 2B4‐mediated NK cell activation: Evidence that human 2B4 is physically and functionally associated with the linker for activation of T cells. Eur. J. Immunol. 30:3718‐3722.
   Bottino, C., Falco, M., Parolini, S., Marcenaro, E., Augugliaro, R., Sivori, S., Landi, E., Biassoni, R., Notarangelo, L.D., Moretta, L., and Moretta, A. 2001. NTB‐A [correction of GNTB‐A], a novel SH2D1A‐associated surface molecule contributing to the inability of natural killer cells to kill Epstein‐Barr virus‐infected B cells in X‐linked lymphoproliferative disease. J. Exp. Med. 194:235‐246.
   Bottino, C., Castriconi, R., Pende, D., Rivera, P., Nanni, M., Carnemolla, B., Cantoni, C., Grassi, J., Marcenaro, S., Reymond, N., Vitale, M., Moretta, L., Lopez, M., and Moretta, A. 2003. Identification of PVR (CD155) and Nectin‐2 (CD112) as cell surface ligands for the human DNAM‐1 (CD226) activating molecule. J. Exp. MEd. 198:557‐567.
   Bottino, C., Castriconi, R., Moretta, L., and Moretta, A. 2005. Cellular ligands of activating NK receptors. Trends Immunol. 26:221‐226.
   Bouchon, A., Cella, M., Grierson, H. L., Cohen, J.I., and Colonna, M. 2001. Activation of NK cell‐mediated cytotoxicity by a SAP‐independent receptor of the CD2 family. J. Immunol. 167:5517‐5521.
   Brandt, C.S., Baratin, M., Yi, E.C., Kennedy, J., Gao, Z., Fox, B., Haldeman, B., Ostrander, C.D., Kaifu, T., Chabannon, C., Moretta, A., West, R., Xu, W., Vivier, E., and Levin, S.D. 2009. The B7 family member B7‐H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J. Exp. Med. 206:1495‐1503.
   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.
   Bryceson, Y.T., March, M.E., Ljunggren, H.G., and Long, E.O. 2006a. Activation, coactivation, and costimulation of resting human natural killer cells. Immunol. Rev. 214:73‐91.
   Bryceson, Y.T., March, M.E., Ljunggren, H.G., and Long, E.O. 2006b. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107:159‐166.
   Bryceson, Y.T., Rudd, E., Zheng, C., Edner, J., Ma, D., Wood, S.M., Bechensteen, A.G., Boelens, J.J., Celkan, T., Farah, R.A., Hultenby, K., Winiarski, J., Roche, P.A., Nordenskjold, M., Henter, J.I., Long, E.O., and Ljunggren, H.G. 2007. Defective cytotoxic lymphocyte degranulation in syntaxin‐11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. Blood 110:1906‐1915.
   Burbach, B.J., Medeiros, R.B., Mueller, K.L., and Shimizu, Y. 2007. T‐cell receptor signaling to integrins. Immunol. Rev. 218:65‐81.
   Burshtyn, D.N., Scharenberg, A.M., Wagtmann, N., Rajagopalan, S., Berrada, K., Yi, T., Kinet, J.P., and Long, E.O. 1996. Recruitment of tyrosine phosphatase HCP (SHP‐1) by the killer cell inhibitor receptor. Immunity 4:77‐85.
   Byrd, A., Hoffmann, S.C., Jarahian, M., Momburg, F., and Watzl, C. 2007. Expression analysis of the ligands for the Natural Killer cell receptors NKp30 and NKp44. PLoS ONE 2:e1339.
   Cantoni, C., Bottino, C., Vitale, M., Pessino, A., Augugliaro, R., Malaspina, A., Parolini, S., Moretta, L., Moretta, A., and Biassoni, R. 1999. NKp44, a triggering receptor involved in tumor cell lysis by activated human natural killer cells, is a novel member of the immunoglobulin superfamily. J. Exp. Med. 189:787‐796.
   Cantor, J.M., Ginsberg, M.H., and Rose, D.M. 2008. Integrin‐associated proteins as potential therapeutic targets. Immunol. Rev. 223:236‐251.
   Caraux, A., Kim, N., Bell, S.E., Zompi, S., Ranson, T., Lesjean‐Pottier, S., Garcia‐Ojeda, M.E., Turner, M., and Colucci, F. 2006. Phospholipase C‐gamma2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells. Blood 107:994‐1002.
   Cella, M., Fujikawa, K., Tassi, I., Kim, S., Latinis, K., Nishi, S., Yokoyama, W., Colonna, M., and Swat, W. 2004. Differential requirements for Vav proteins in DAP10‐ and ITAM‐mediated NK cell cytotoxicity. J. Exp. Med. 200:817‐823.
   Chan, B., Lanyi, A., Song, H.K., Griesbach, J., Simarro‐Grande, M., Poy, F., Howie, D., Sumegi, J., Terhorst, C., and Eck, M.J. 2003. SAP couples Fyn to SLAM immune receptors. Nat. Cell. Biol. 5:155‐160.
   Chan, G., Hanke, T., and Fischer, K.D. 2001. Vav‐1 regulates NK T cell development and NK cell cytotoxicity. Eur. J. Immunol. 31:2403‐2410.
   Chen, R., Relouzat, F., Roncagalli, R., Aoukaty, A., Tan, R., Latour, S., and Veillette, A. 2004. Molecular dissection of 2B4 signaling: Implications for signal transduction by SLAM‐related receptors. Mol. Cell. Biol. 24:5144‐5156.
   Cherukuri, A., Dykstra, M., and Pierce, S.K. 2001. Floating the raft hypothesis: Lipid rafts play a role in immune cell activation. Immunity 14:657‐660.
   Chiesa, S., Mingueneau, M., Fuseri, N., Malissen, B., Raulet, D.H., Malissen, M., Vivier, E., and Tomasello, E. 2006. Multiplicity and plasticity of natural killer cell signaling pathways. Blood 107:2364‐2372.
   Chlewicki, L.K., Velikovsky, C.A., Balakrishnan, V., Mariuzza, R.A., and Kumar, V. 2008. Molecular basis of the dual functions of 2B4 (CD244). J. Immunol. 180:8159‐8167.
   Ciccone, E., Pende, D., Viale, O., Than, A., Di Donato, C., Orengo, A.M., Biassoni, R., Verdiani, S., Amoroso, A., Moretta, A., and Moretta, L. 1992. Involvement of HLA class I alleles in natural killer (NK) cell‐specific functions: expression of HLA‐Cw3 confers selective protection from lysis by alloreactive NK clones displaying a defined specificity (specificity 2). J. Exp. Med. 176:963‐971.
   Claus, M., Meinke, S., Bhat, R., and Watzl, C. 2008. Regulation of NK cell activity by 2B4, NTB‐A and CRACC. Front Biosci. 13:956‐965.
   Colucci, F., Rosmaraki, E., Bregenholt, S., Samson, S.I., Di Bartolo, V., Turner, M., Vanes, L., Tybulewicz, V., and Di Santo, J.P. 2001. Functional dichotomy in natural killer cell signaling: Vav1‐dependent and ‐independent mechanisms. J. Exp. Med. 193:1413‐1424.
   Colucci, F., Schweighoffer, E., Tomasello, E., Turner, M., Ortaldo, J.R., Vivier, E., Tybulewicz, V.L., and Di Santo, J.P. 2002. Natural cytotoxicity uncoupled from the Syk and ZAP‐70 intracellular kinases. Nat. Immunol. 3:288‐294.
   Combs, J., Kim, S.J., Tan, S., Ligon, L.A., Holzbaur, E.L., Kuhn, J., and Poenie, M. 2006. Recruitment of dynein to the Jurkat immunological synapse. Proc. Natl. Acad. Sci. U.S.A. 103:14883‐14888.
   Cooper, M.A., Fehniger, T.A., Turner, S.C., Chen, K.S., Ghaheri, B.A., Ghayur, T., Carson, W.E., and Caligiuri, M.A. 2001. Human natural killer cells: A unique innate immunoregulatory role for the CD56bright subset. Blood 97:3146‐3151.
   Cruz‐Munoz, M.E., Dong, Z., Shi, X., Zhang, S., and Veillette, A. 2009. Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT‐2, on natural killer cell function. Nat. Immunol. 10:297‐305.
   Davis, S.J., Ikemizu, S., Wild, M.K., and van der Merwe, P.A. 1998. CD2 and the nature of protein interactions mediating cell‐cell recognition. Immunol. Rev. 163:217‐236.
   Diefenbach, A., Tomasello, E., Lucas, M., Jamieson, A.M., Hsia, J.K., Vivier, E., and Raulet, D.H. 2002. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nat. Immunol. 3:1142‐1149.
   Eissmann, P. and Watzl, C. 2006. Molecular analysis of NTB‐A signaling: A role for EAT‐2 in NTB‐A‐mediated activation of human NK cells. J. Immunol. 177:3170‐3177.
   Eissmann, P., Beauchamp, L., Wooters, J., Tilton, J.C., Long, E.O., and Watzl, C. 2005. Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244). Blood 105:4722‐4729.
   Eleme, K., Taner, S.B., Onfelt, B., Collinson, L.M., McCann, F.E., Chalupny, N.J., Cosman, D., Hopkins, C., Magee, A.I., and Davis, D.M. 2004. Cell surface organization of stress‐inducible proteins ULBP and MICA that stimulate human NK cells and T cells via NKG2D. J. Exp. Med. 199:1005‐1010.
   Endt, J., McCann, F.E., Almeida, C.R., Urlaub, D., Leung, R., Pende, D., Davis, D.M., and Watzl, C. 2007. Inhibitory receptor signals suppress ligation‐induced recruitment of NKG2D to GM1‐rich membrane domains at the human NK cell immune synapse. J. Immunol. 178:5606‐5611.
   Fischer, A., Latour, S., and de Saint Basile, G. 2007. Genetic defects affecting lymphocyte cytotoxicity. Curr. Opin. Immunol. 19:348‐353.
   Fostel, L.V., Dluzniewska, J., Shimizu, Y., Burbach, B.J., and Peterson, E.J. 2006. ADAP is dispensable for NK cell development and function. Int. Immunol. 18:1305‐1314.
   Galandrini, R., Micucci, F., Tassi, I., Cifone, M.G., Cinque, B., Piccoli, M., Frati, L., and Santoni, A. 2005. Arf6: A new player in FcgammaRIIIA lymphocyte‐mediated cytotoxicity. Blood 106:577‐583.
   Garrity, D., Call, M.E., Feng, J., and Wucherpfennig, K.W. 2005. The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure. Proc. Natl. Acad. Sci. U.S.A. 102:7641‐7646.
   Gasser, S., and Raulet, D.H. 2006. Activation and self‐tolerance of natural killer cells. Immunol. Rev. 214:130‐142.
   Gasser, S., Orsulic, S., Brown, E.J., and Raulet, D.H. 2005. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436:1186‐1190.
   Geiger, C., Nagel, W., Boehm, T., van Kooyk, Y., Figdor, C.G., Kremmer, E., Hogg, N., Zeitlmann, L., Dierks, H., Weber, K.S., and Kolanus, W. 2000. Cytohesin‐1 regulates beta‐2 integrin‐mediated adhesion through both ARF‐GEF function and interaction with LFA‐1. EMBO J. 19:2525‐2536.
   Gilfillan, S., Chan, C.J., Cella, M., Haynes, N.M., Rapaport, A.S., Boles, K.S., Andrews, D.M., Smyths, M.J., and Colonna, M. 2008. DNAM‐1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen‐presenting cells and tumors. J. Exp. Med. 205:2965‐2973.
   Gismondi, A., Bisogno, L., Mainiero, F., Palmieri, G., Piccoli, M., Frati, L., and Santoni, A. 1997. Proline‐rich tyrosine kinase‐2 activation by b1 integrin fibronectin receptor cross‐linking and association with paxillin in human natural killer cells. J. Immunol. 159:4729‐4736.
   Gismondi, A., Jacobelli, J., Strippoli, R., Mainiero, F., Soriani, A., Cifaldi, L., Piccoli, M., Frati, L., and Santoni, A. 2003. Proline‐rich tyrosine kinase 2 and Rac activation by chemokine and integrin receptors controls NK cell transendothelial migration. J. Immunol. 170:3065‐3073.
   Gismondi, A., Cifaldi, L., Mazza, C., Giliani, S., Parolini, S., Morrone, S., Jacobelli, J., Bandiera, E., Notarangelo, L., and Santoni, A. 2004. Impaired natural and CD16‐mediated NK cell cytotoxicity in patients with WAS and XLT: Ability of IL‐2 to correct NK cell functional defect. Blood 104:436‐443.
   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.
   Guerra, N., Tan, Y.X., Joncker, N.T., Choy, A., Gallardo, F., Xiong, N., Knoblaugh, S., Cado, D., Greenberg, N.M., and Raulet, D.H. 2008. NKG2D‐deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28:571‐580.
   Hanna, J., Goldman‐Wohl, D., Hamani, Y., Avraham, I., Greenfield, C., Natanson‐Yaron, S., Prus, D., Cohen‐Daniel, L., Arnon, T.I., Manaster, I., Gazit, R., Yutkin, V., Benharroch, D., Porgador, A., Keshet, E., Yagel, S., and Mandelboim, O. 2006. Decidual NK cells regulate key developmental processes at the human fetal‐maternal interface. Nat. Med. 12:1065‐1074.
   Hidalgo, A. and Frenette, P.S. 2009. When integrins fail to integrate. Nat. Med. 15:249‐250.
   Iguchi‐Manaka, A., Kai, H., Yamashita, Y., Shibata, K., Tahara‐Hanaoka, S., Honda, S., Yasui, T., Kikutani, H., Shibuya, K., and Shibuya, A. 2008. Accelerated tumor growth in mice deficient in DNAM‐1 receptor. J. Exp. Med. 205:2959‐2964.
   Jakus, Z., Fodor, S., Abram, C.L., Lowell, C.A., and Mocsai, A. 2007. Immunoreceptor‐like signaling by beta 2 and beta 3 integrins. Trends Cell Biol. 17:493‐501.
   Jiang, K., Zhong, B., Gilvary, D.L., Corliss, B.C., Hong‐Geller, E., Wei, S., and Djeu, J.Y. 2000. Pivotal role of phosphoinositide‐3 kinase in regulation of cytotoxicity in natural killer cells. Nat. Immunol. 1:419‐425.
   Joncker, N.T. and Raulet, D.H. 2008. Regulation of NK cell responsiveness to achieve self‐tolerance and maximal responses to diseased target cells. Immunol. Rev. 224:85‐97.
   Karlhofer, F.M., Ribaudo, R.K., and Yokoyama, W.M. 1992. MHC class I alloantigen specificity of Ly‐49+ IL‐2‐activated natural killer cells. Nature 358:66‐70.
   Kielczewska, A., Pyzik, M., Sun, T., Krmpotic, A., Lodoen, M.B., Munks, M.W., Babic, M., Hill, A.B., Koszinowski, U.H., Jonjic, S., Lanier, L.L., and Vidal, S.M. 2009. Ly49P recognition of cytomegalovirus‐infected cells expressing H2‐Dk and CMV‐encoded m04 correlates with the NK cell antiviral response. J. Exp. Med. 206:515‐523.
   Krzewski, K., Chen, X., and Strominger, J.L. 2008. WIP is essential for lytic granule polarization and NK cell cytotoxicity. Proc. Natl. Acad. Sci. U.S.A. 105:2568‐2573.
   Kuttruff, S., Koch, S., Kelp, A., Pawelec, G., Rammensee, H.G., and Steinle, A. 2009. NKp80 defines and stimulates a reactive subset of CD8 T cells. Blood 113:358‐369.
   Lanier, L.L. 2005. NK cell recognition. Annu. Rev. Immunol. 23:225‐274.
   Lanier, L.L., Yu, G., and Phillips, J.H. 1991. Analysis of Fc gamma RIII (CD16) membrane expression and association with CD3 zeta and Fc epsilon RI‐gamma by site‐directed mutation. J. Immunol. 146:1571‐1576.
   Lanier, L.L., Corliss, B.C., Wu, J., Leong, C., and Phillips, J.H. 1998a. Immunoreceptor DAP12 bearing a tyrosine‐based activation motif is involved in activating NK cells. Nature 391:703‐707.
   Lanier, L.L., Corliss, B., Wu, J., and Phillips, J.H. 1998b. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity 8:693‐701.
   Latour, S., Roncagalli, R., Chen, R., Bakinowski, M., Shi, X., Schwartzberg, P.L., Davidson, D., and Veillette, A. 2003. Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation. Nat. Cell. Biol. 5:149‐154.
   Lee, S.H., Miyagi, T., and Biron, C.A. 2007. Keeping NK cells in highly regulated antiviral warfare. Trends Immunol. 28:252‐259.
   Li, J., Nishizawa, K., An, W., Hussey, R.E., Lialios, F.E., Salgia, R., Sunder‐Plassmann, R., and Reinherz, E.L. 1998. A cdc15‐like adaptor protein (CD2BP1) interacts with the CD2 cytoplasmic domain and regulates CD2‐triggered adhesion. EMBO J. 17:7320‐7336.
   Li, C., Ge, B., Nicotra, M., Stern, J.N., Kopcow, H.D., Chen, X., and Strominger, J.L. 2008. JNK MAP kinase activation is required for MTOC and granule polarization in NKG2D‐mediated NK cell cytotoxicity. Proc. Natl. Acad. Sci. U.S.A. 105:3017‐3022.
   Ljunggren, H.G. and Kärre, K. 1985. Host resistance directed selectively against H‐2‐deficient lymphoma variants. Analysis of the mechanism. J. Exp. Med. 162:1745‐1759.
   Long, E.O. 2008. Negative signaling by inhibitory receptors: The NK cell paradigm. Immunol. Rev. 224:70‐84.
   Mace, E.M., Monkley, S.J., Critchley, D.R., and Takei, F. 2009. A dual role for talin in NK cell cytotoxicity: Activation of LFA‐1‐mediated cell adhesion and polarization of NK cells. J. Immunol. 182:948‐956.
   Mainiero, F., Gismondi, A., Soriani, A., Cippitelli, M., Palmieri, G., Jacobelli, J., Piccoli, M., Frati, L., and Santoni, A. 1998. Integrin‐mediated Ras‐extracellular regulated kinase (ERK) signaling regulates interferon gamma production in human natural killer cells. J. Exp. Med. 188:1267‐1275.
   Mainiero, F., Soriani, A., Strippoli, R., Jacobelli, J., Gismondi, A., Piccoli, M., Frati, L., and Santoni, A. 2000. RAC1/P38 MAPK signaling pathway controls β1 integrin‐induced interleukin‐8 production in human natural killer cells. Immunity 12:7‐16.
   Marcenaro, S., Gallo, F., Martini, S., Santoro, A., Griffiths, G.M., Arico, M., Moretta, L., and Pende, D. 2006. Analysis of natural killer‐cell function in familial hemophagocytic lymphohistiocytosis (FHL): Defective CD107a surface expression heralds Munc13‐4 defect and discriminates between genetic subtypes of the disease. Blood 108:2316‐2323.
   Mason, L.H., Willette‐Brown, J., Taylor, L.S., and McVicar, D.W. 2006. Regulation of Ly49D/DAP12 signal transduction by Src‐family kinases and CD45. J. Immunol. 176:6615‐6623.
   Menasche, G., Kliche, S., Chen, E.J., Stradal, T.E., Schraven, B., and Koretzky, G. 2007. RIAM links the ADAP/SKAP‐55 signaling module to Rap1, facilitating T‐cell‐receptor‐mediated integrin activation. Mol. Cell Biol. 27:4070‐4081.
   Micucci, F., Capuano, C., Marchetti, E., Piccoli, M., Frati, L., Santoni, A., and Galandrini, R. 2008. PI5KI‐dependent signals are critical regulators of the cytolytic secretory pathway. Blood 111:4165‐4172.
   Miranti, C.K., Leng, L., Maschberger, P., Brugge, J.S., and Shattil, S.J. 1998. Identification of a novel integrin signaling pathway involving the kinase Syk and the guanine nucleotide exchange factor Vav1. Curr. Biol. 8:1289‐1299.
   Mor, A., Dustin, M.L., and Philips, M.R. 2007. Small GTPases and LFA‐1 reciprocally modulate adhesion and signaling. Immunol. Rev. 218:114‐125.
   Moretta, A., Marcenaro, E., Parolini, S., Ferlazzo, G., and Moretta, L. 2008. NK cells at the interface between innate and adaptive immunity. Cell Death Differ. 15:226‐233.
   Nakajima, H., Cella, M., Bouchon, A., Grierson, H.L., Lewis, J., Duckett, C.S., Cohen, J.I., and Colonna, M. 2000. Patients with X‐linked lymphoproliferative disease have a defect in 2B4 receptor‐mediated NK cell cytotoxicity. Eur. J. Immunol. 30:3309‐3318.
   Nguyen, K.B., Watford, W.T., Salomon, R., Hofmann, S.R., Pien, G.C., Morinobu, A., Gadina, M., O'Shea, J.J., and Biron, C.A. 2002. Critical role for STAT4 activation by type 1 interferons in the interferon‐gamma response to viral infection. Science 297:2063‐2066.
   Nichols, K.E., Ma, C.S., Cannons, J.L., Schwartzberg, P.L., and Tangye, S.G. 2005. Molecular and cellular pathogenesis of X‐linked lymphoproliferative disease. Immunol. Rev. 203:180‐199.
   Nolz, J.C., Medeiros, R.B., Mitchell, J.S., Zhu, P., Freedman, B.D., Shimizu, Y., and Billadeau, D.D. 2007. WAVE2 regulates high‐affinity integrin binding by recruiting vinculin and talin to the immunological synapse. Mol. Cell. Biol. 27:5986‐6000.
   Nolz, J.C., Nacusi, L.P., Segovis, C.M., Medeiros, R.B., Mitchell, J.S., Shimizu, Y., and Billadeau, D.D. 2008. The WAVE2 complex regulates T cell receptor signaling to integrins via Abl‐ and CrkL‐C3G‐mediated activation of Rap1. J. Cell Biol. 182:1231‐1244.
   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. 2002a. Wiskott‐Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell‐activating immunologic synapses. Proc. Natl. Acad. Sci. U.S.A. 99:11351‐11356.
   Orange, J.S., Brodeur, S.R., Jain, A., Bonilla, F.A., Schneider, L.C., Kretschmer, R., Nurko, S., Rasmussen, W.L., Köhler, J.R., Gellis, S.E., Ferguson, B.M., Strominger, J.L., Zonana, J., Ramesh, N., Ballas, Z.K., and Geha, R.S. 2002b. Deficient natural killer cell cytotoxicity in patients with IKK‐gamma/NEMO mutations. J. Clin. Invest. 109:1501‐1509.
   Orange, J.S. 2008. Formation and function of the lytic NK‐cell immunological synapse. Nat. Rev. Immunol. 8:713‐725.
   Parolini, S., Bottino, C., Falco, M., Augugliaro, R., Giliani, S., Franceschini, R., Ochs, H.D., Wolf, H., Bonnefoy, J.Y., Biassoni, R., Moretta, L., Notarangelo, L.D., and Moretta, A. 2000. X‐linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein‐Barr virus‐infected cells. J. Exp. Med. 192:337‐346.
   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.
   Peterson, M.E. and Long, E.O. 2008. Inhibitory receptor signaling via tyrosine phosphorylation of the adaptor Crk. Immunity 29:578‐588.
   Porter, J.C., Bracke, M., Smith, A., Davies, D., and Hogg, N. 2002. Signaling through integrin LFA‐1 leads to filamentous actin polymerization and remodeling, resulting in enhanced T cell adhesion. J. Immunol. 168:6330‐6335.
   Rajagopalan, S., Bryceson, Y.T., Kuppusamy, S.P., Geraghty, D.E., van der Meer, A., Joosten, I., and Long, E.O. 2006. Activation of NK cells by an endocytosed receptor for soluble HLA‐G. PLoS Biol. 4:e9.
   Ralston, K.J., Hird, S.L., Zhang, X., Scott, J.L., Jin, B., Thorne, R.F., Berndt, M.C., Boyd, A.W., and Burns, G.F. 2004. The LFA‐1‐associated molecule PTA‐1 (CD226) on T cells forms a dynamic molecular complex with protein 4.1G and human discs large. J. Biol. Chem. 279:33816‐33828.
   Regunathan, J., Chen, Y., Kutlesa, S., Dai, X., Bai, L., Wen, R., Wang, D., and Malarkannan, S. 2006. Differential and nonredundant roles of phospholipase Cgamma2 and phospholipase Cgamma1 in the terminal maturation of NK cells. J. Immunol. 177:5365‐5376.
   Riteau, B., Barber, D.F., and Long, E.O. 2003. Vav1 phosphorylation is induced by beta2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. J. Exp. Med. 198:469‐474.
   Roncagalli, R., Taylor, J.E., Zhang, S., Shi, X., Chen, R., Cruz‐Munoz, M.E., Yin, L., Latour, S., and Veillette, A. 2005. Negative regulation of natural killer cell function by EAT‐2, a SAP‐related adaptor. Nat. Immunol. 6:1002‐1010.
   Saborit‐Villarroya, I., Del Valle, J.M., Romero, X., Esplugues, E., Lauzurica, P., Engel, P., and Martin, M. 2005. The adaptor protein 3BP2 binds human CD244 and links this receptor to Vav signaling, ERK activation, and NK cell killing. J. Immunol. 175:4226‐4235.
   Sancho, D., Nieto, M., Llano, M., Rodríguez‐Fernández, J.L., Tejedor, R., Avraham, S., Cabañas, C., López‐Botet, M., and Sánchez‐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. 149:1249‐1261.
   Sayos, J., Wu, C., Morra, M., Wang, N., Zhang, X., Allen, D., van Schaik, S., Notarangelo, L., Geha, R., Roncarolo, M.G., Oettgen, H., De Vries, J.E., Aversa, G., and Terhorst, C. 1998. The X‐linked lymphoproliferative‐disease gene product SAP regulates signals induced through the co‐receptor SLAM. Nature 395:462‐469.
   Shibuya, A., Campbell, D., Hannum, C., Yssel, H., Franz‐Bacon, K., McClanahan, T., Kitamura, T., Nicholl, J., Sutherland, G.R., Lanier, L.L., and Phillips, J.H. 1996. DNAM‐1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 4:573‐581.
   Shibuya, K., Shirakawa, J., Kameyama, T., Honda, S., Tahara‐Hanaoka, S., Miyamoto, A., Onodera, M., Sumida, T., Nakauchi, H., Miyoshi, H., and Shibuya, A. 2003. CD226 (DNAM‐1) is involved in lymphocyte function‐associated antigen 1 costimulatory signal for naive T cell differentiation and proliferation. J. Exp. Med. 198:1829‐1839.
   Sirim, P., Zeitlmann, L., Kellersch, B., Falk, C.S., Schendel, D.J., and Kolanus, W. 2001. Calcium signaling through the beta2‐cytoplasmic domain of LFA‐1 requires intracellular elements of the T cell receptor complex. J. Biol. Chem. 276:42945‐42956.
   Sivori, S., Falco, M., Marcenaro, E., Parolini, S., Biassoni, R., Bottino, C., Moretta, L., and Moretta, A. 2002. Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation. Proc. Natl. Acad. Sci. U.S.A. 99:4526‐4531.
   Smith, H.R.C., Heusel, J.W., Mehta, I.K., Kim, S., Dorner, B.G., Naidenko, O.V., Iizuka, K., Furukawa, H., Beckman, D.L., Pingel, J.T., Scalzo, A.A., Fremont, D.H., and Yokoyama, W.M. 2002. Recognition of a virus‐encoded ligand by a natural killer cell activation receptor. Proc. Natl. Acad. Sci. U.S.A. 99:8826‐8831.
   Smith, K.M., Wu, J., Bakker, A.B., Phillips, J.H., and Lanier, L.L. 1998. Ly‐49D and Ly‐49H associate with mouse DAP12 and form activating receptors. J. Immunol. 161:7‐10.
   Smyth, M.J., Hayakawa, Y., Takeda, K., and Yagita, H. 2002. New aspects of natural‐killer‐cell surveillance and therapy of cancer. Nat. Rev. Cancer 2:850‐861.
   Stinchcombe, J.C. and Griffiths, G.M. 2007. Secretory mechanisms in cell‐mediated cytotoxicity. Annu. Rev. Cell Dev. Biol. 23:495‐517.
   Strowig, T., Brilot, F., and Munz, C. 2008. Noncytotoxic functions of NK cells: Direct pathogen restriction and assistance to adaptive immunity. J. Immunol. 180:7785‐7791.
   Tahara‐Hanaoka, S., Shibuya, K., Onoda, Y., Zhang, H., Yamazaki, S., Miyamoto, A., Honda, S., Lanier, L.L., and Shibuya, A. 2004. Functional characterization of DNAM‐1 (CD226) interaction with its ligands PVR (CD155) and nectin‐2 (PRR‐2/CD112). Int. Immunol. 16:533‐538.
   Tangye, S.G., Phillips, J.H., Lanier, L.L., and Nichols, K.E. 2000. Functional requirement for SAP in 2B4‐mediated activation of human natural killer cells as revealed by the X‐linked lymphoproliferative syndrome. J. Immunol. 165:2932‐2936.
   Tassi, I., Klesney‐Tait, J., and Colonna, M. 2006. Dissecting natural killer cell activation pathways through analysis of genetic mutations in human and mouse. Immunol. Rev. 214:92‐105.
   Tassi, I., Presti, R., Kim, S., Yokoyama, W.M., Gilfillan, S., and Colonna, M. 2005. Phospholipase C‐gamma 2 is a critical signaling mediator for murine NK cell activating receptors. J. Immunol. 175:749‐754.
   Ting, A.T., Karnitz, L.M., Schoon, R.A., Abraham, R.T., and Leibson, P.J. 1992. Fcγ receptor activation induces the tyrosine phosphorylation of both phospholipase C (PLC)‐γ1 and PLC‐γ2 in natural killer cells. J. Exp. Med. 176:1751‐1755.
   Upshaw, J.L., Schoon, R.A., Dick, C.J., Billadeau, D.D., and Leibson, P.J. 2005. The isoforms of phospholipase C‐gamma are differentially used by distinct human NK activating receptors. J. Immunol. 175:213‐218.
   Upshaw, J.L., Arneson, L.N., Schoon, R.A., Dick, C.J., Billadeau, D.D., and Leibson, P.J. 2006. NKG2D‐mediated signaling requires a DAP10‐bound Grb2‐Vav1 intermediate and phosphatidylinositol‐3‐kinase in human natural killer cells. Nat. Immunol. 7:524‐532.
   van Oers, N.S., Lowin‐Kropf, B., Finlay, D., Connolly, K., and Weiss, A. 1996. Alpha beta T cell development is abolished in mice lacking both Lck and Fyn protein tyrosine kinases. Immunity 5:429‐436.
   Veillette, A. 2006. NK cell regulation by SLAM family receptors and SAP‐related adapters. Immunol. Rev. 214:22‐34.
   Vitale, M., Falco, M., Castriconi, R., Parolini, S., Zambello, R., Semenzato, G., Biassoni, R., Bottino, C., Moretta, L., and Moretta, A. 2001. Identification of NKp80, a novel triggering molecule expressed by human NK cells. Eur. J. Immunol. 31:233‐242.
   Vivier, E., Spits, H., and Cupedo, T. 2009. Interleukin‐22‐producing innate immune cells: New players in mucosal immunity and tissue repair? Nat. Rev. Immunol. 9:229‐234.
   Walzer, T., Jaeger, S., Chaix, J., and Vivier, E. 2007. Natural killer cells: from CD3(‐)NKp46(+) to post‐genomics meta‐analyses. Curr. Opin. Immunol. 19:365‐372.
   Wang, H. and Rudd, C.E. 2008. SKAP‐55, SKAP‐55‐related and ADAP adaptors modulate integrin‐mediated immune‐cell adhesion. Trends Cell Biol. 18:486‐493.
   Watzl, C. and Long, E.O. 2003. Natural killer cell inhibitory receptors block actin cytoskeleton‐dependent recruitment of 2B4 (CD244) to lipid rafts. J. Exp. Med. 197:77‐85.
   Watzl, C., Stebbins, C.C., and Long, E.O. 2000. NK cell inhibitory receptors prevent tyrosine phosphorylation of the activation receptor 2B4 (CD244). J. Immunol. 165:3545‐3548.
   Welte, S., Kuttruff, S., Waldhauer, I., and Steinle, A. 2006. Mutual activation of natural killer cells and monocytes mediated by NKp80‐AICL interaction. Nat. Immunol. 7:1334‐1342.
   Woodside, D.G., Obergfell, A., Talapatra, A., Calderwood, D.A., Shattil, S.J., and Ginsberg, M.H. 2002. The N‐terminal SH2 domains of Syk and ZAP‐70 mediate phosphotyrosine‐independent binding to integrin beta cytoplasmic domains. J. Biol. Chem. 277:39401‐39408.
   Wu, C.Y. and Dedhar, S. 2001. Integrin‐linked kinase (ILK) and its interactors: A new paradigm for the coupling of extracellular matrix to actin cytoskeleton and signaling complexes. J. Cell Biol. 155:505‐510.
   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.
   Yokoyama, W.M. and Kim, S. 2006. Licensing of natural killer cells by self‐major histocompatibility complex class I. Immunol. Rev. 214:143‐154.
   Yu, M.C., Su, L.L., Zou, L., Liu, Y., Wu, N., Kong, L., Zhuang, Z.H., Sun, L., Liu, H.P., Hu, J.H., Li, D., Strominger, J.L., Zang, J.W., Pei, G., and Ge, B.X. 2008. An essential function for beta‐arrestin 2 in the inhibitory signaling of natural killer cells. Nat. Immunol. 9:898‐907.
   Zompi, S., Hamerman, J.A., Ogasawara, K., Schweighoffer, E., Tybulewicz, V.L., Di Santo, J.P., Lanier, L.L., and Colucci, F. 2003. NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases. Nat. Immunol. 4:565‐572.
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