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• W2021406365 abstract "When once your point of view is changed, the very thing which was so damning becomes a clue to the truth.—Sherlock Holmes Natural killer (NK) cells are a subpopulation of phenotypically identifiable lymphocytes (CD16+, CD3−, sIg−) that can mediate the lysis of certain tumor cells and virus-infected cells and that can secrete certain cytokines upon activation (e.g., γ-interferon, tumor necrosis factor, granulocyte/macrophage colony-stimulating factor, and macrophage colony-stimulating factor) (102Trinchieri G Adv. Immunol. 1989; 74: 187-376Crossref Scopus (2623) Google Scholar, 103Trinchieri G Semin. Immunol. 1995; 7: 83-88Crossref PubMed Scopus (126) Google Scholar). These biological responses enable NK cells to provide resistance against infectious microorganisms, control malignant growth, modulate other immune cells, and regulate hematopoietic cell differentiation. The execution of these effector functions is initiated when receptors on NK cells bind to specific soluble or cell-associated ligands. The translation of these recognition events into intracellular biochemical signals regulates NK cell functional responses. It is tempting to suggest that NK cells are simply another type of lymphocyte bearing multisubunit immune recognition receptors and that their signaling mechanisms are therefore likely to recapitulate those described for T or B lymphocytes. This generalist view is also fueled by the recognition that NK cells and T cells share a common progenitor (97Spits H Lanier L.L Phillips J.H Blood. 1995; 85: 2654-2670PubMed Google Scholar) and that many NK cell surface receptors are expressed on subsets of T cells (102Trinchieri G Adv. Immunol. 1989; 74: 187-376Crossref Scopus (2623) Google Scholar). Yet a series of recent experimental observations highlights the inadequacy of this derivative perspective. For example, whereas the Src-family tyrosine kinase Lck and the cell surface tyrosine phosphatase CD45 are essential for T cell receptor (TCR)–initiated signaling, these molecules, which are also expressed by normal NK cells, are not required for NK cell Fc receptor (FcR)–mediated killing or natural cytotoxicity (63Molina T.J Kishihara K Siderovski D.P van Ewijk W Narendran A Timms E Wakeham A Paige C.J Hartmann K.-U Veillette A et al.Nature. 1992; 357: 161-164Crossref PubMed Scopus (872) Google Scholar, 111Wen T Zhang L Kung S.K Molina T.J Miller R.G Mak T.W Eur. J. Immunol. 1995; 25: 3155-3159Crossref PubMed Scopus (41) Google Scholar, 105van Oers N.S.C Lowin-Kropf B Finlay D Connolly K Weiss A Immunity. 1996; 5: 429-436Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, 113Yamada H Kishihara K Kong Y.-Y Momoto K J. Immunol. 1996; 157: 1523-1528PubMed Google Scholar). Similarly, the Syk-family tyrosine kinase ZAP-70, which is expressed by both T cells and NK cells, is required for TCR-initiated signaling but not for NK cell cytotoxic function (24Chen A.C Kadlecek T.A Elder M.E Filipovich A.H Kuo W.-L Iwashima M Parslow T.G Weiss A Science. 1994; 264: 1599-1601Crossref PubMed Scopus (412) Google Scholar, 68Negishi I Motoyama N Nakayama K.-I Nakayama K Senju S Hatakeyama S Zhang Q Chan A.C Loh D.Y Nature. 1995; 376: 435-438Crossref PubMed Scopus (456) Google Scholar). In addition, recent observations have highlighted the central role for novel major histocompatibility complex (MHC)–recognizing inhibitory receptors in determining the capacity of NK cells to initiate cellular activation (55Ljunggren H.-G Karre K Immunol. Today. 1990; 11: 237-244Abstract Full Text PDF PubMed Scopus (391) Google Scholar, 53Leibson P.J Immunity. 1995; 3: 5-8Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 49Lanier L.L Phillips J.H Immunol. Today. 1996; 17: 86-91Abstract Full Text PDF PubMed Scopus (292) Google Scholar, 66Moretta A Bottino C Vitale M Pende D Biassoni R Mingari M.C Moretta L Annu. Rev. Immunol. 1996; 14: 619-648Crossref PubMed Scopus (743) Google Scholar, 12Brown M.G Scalzo A.A Matsumoto K Yokoyama W.M Immunol. Rev. 1997; 155: 53-65Crossref PubMed Scopus (146) Google Scholar, 26Colonna M Immunol. Rev. 1997; 155: 127-133Crossref PubMed Scopus (104) Google Scholar, 57Long E.O Burshtyn D.N Clark W.P Peruzzi M Rajagopalan S Rojo S Wagtmann N Winter C.C Immunol. Rev. 1997; 155: 135-144Crossref PubMed Scopus (194) Google Scholar, 86Raulet D.H Weld W Correa I Dorfman J Wu M.-F Corral L Immunol. Rev. 1997; 155: 41-52Crossref PubMed Scopus (196) Google Scholar, 88Renard V Cambiaggi A Vely F Blery M Olcese L Olivero S Bouchet M Vivier E Immunol. Rev. 1997; 155: 205-221Crossref PubMed Scopus (103) Google Scholar). This minireview focuses on a description and analysis of the signaling mechanisms that critically influence the specialized cytotoxic function of NK cells: FcγRIII-initiated antibody-dependent cellular cytotoxicity (ADCC) and natural killing. Information is provided to suggest that it is the balance between key positive and negative regulatory events that determines the capacity of NK cells to kill. ADCC mediated by NK cells is initiated by engagement of low-affinity FcγRIIIA by the Fc portion of antibodies bound to cell-associated antigens. FcγRIIIA on human NK cells is a multimeric receptor complex consisting of the ligand-binding α subunit (CD16), which associates noncovalently with homodimers or heterodimers of ζ and γ (Figure 1) (2Anderson P Caligiuri M Ritz J Schlossman S.F Nature. 1989; 341: 159-162Crossref PubMed Scopus (179) Google Scholar, 50Lanier L.L Yu G Phillips J.H Nature. 1989; 342: 803-805Crossref PubMed Scopus (309) Google Scholar, 72Orloff D.G Ra C Frank S.J Klausner R.D Kinet J.-P Nature. 1990; 347: 189-191Crossref PubMed Scopus (199) Google Scholar, 47Kurosaki T Gander I Ravetch J.V Proc. Natl. Acad. Sci. USA. 1991; 88: 3837-3841Crossref PubMed Scopus (115) Google Scholar). Although none of the subunits of the receptor complex possesses intrinsic kinase activity, conserved immunoreceptor tyrosine-based activation motifs (ITAMs) (consensus amino acid sequence YXXL-X(6–8)-YXXL) in the ζ and γ subunits are critical for the rapid generation of intracellular second messengers (89Reth M Nature. 1989; 338: 383-384Crossref PubMed Scopus (1136) Google Scholar, 17Cambier J.C J. Immunol. 1995; 155: 3281-3285PubMed Google Scholar). The structural context of the ITAMs in the ζ-γ–containing human FcγRIII complex is different from all ζ-γ–containing multisubunit immune recognition receptors. Although the TCR complex can express both ζ and γ, additional subunits in the complex (CD3-γ, CD3-δ, and CD3-ε) contain ITAMs, and these motifs may quantitatively or qualitatively alter the signals from the TCR (110Weiss A Littman D.R Cell. 1994; 76: 263-274Abstract Full Text PDF PubMed Scopus (1921) Google Scholar, 78Paolini R Renard V Vivier E Oschiai K Jouvin M.-H Malissen B Kinet J.-P J. Exp. Med. 1995; 181: 247-255Crossref PubMed Scopus (38) Google Scholar, 109Wange R.L Samelson L.E Immunity. 1996; 5: 197-205Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar). The high-affinity receptor for immunoglobulin E (FcεRI) has only γ homodimers with a signal-amplifying ITAM-containing β chain (87Ravetch J.V Kinet J.-P Annu. Rev. Immunol. 1991; 9: 457-492Crossref PubMed Scopus (1254) Google Scholar). Although structural homology among the various ITAM-containing subunits has permitted investigators to demonstrate some degree of functional overlap in experimental systems, key differences in signaling and functional responses have been observed. These differences were recently underscored by the demonstrations that different ITAMs can bind different intracellular signaling molecules (including ZAP-70, Syk, phosphlipase C-γ1 [PLC-γ1], and phosphatidylinositol 3-kinase [PI3K]) (30Exley M Varticovski L Peter M Sancho J Terhorst C J. Biol. Chem. 1994; 269: 15140-15146Abstract Full Text PDF PubMed Google Scholar, 18Cambier J.C Johnson S.A Immunol. Lett. 1995; 44: 77-80Crossref PubMed Scopus (20) Google Scholar, 40Isakov N Wange R.L Burgess W.H Watts J.D Aebersold R Samelson L.E J. Exp. Med. 1995; 181: 375-380Crossref PubMed Scopus (161) Google Scholar, 76Osman N Turner H Lucas S Reif K Cantrell D.A Eur. J. Immunol. 1996; 26: 1063-1068Crossref PubMed Scopus (85) Google Scholar). This heterogeneity suggests the potential for different ITAM-containing subunits to couple to separate signaling pathways. In NK cells, the principal focus is on the ITAM-containing γ subunit, since murine FcγRIII contains only γ-γ homodimers (46Kurosaki T Ravetch J.V Nature. 1989; 342: 805-807Crossref PubMed Scopus (145) Google Scholar) and since γ−/− mice, but not ζ−/− mice, have lost their ability to mediate ADCC (54Liu C.-P Ueda R She J Sancho J Wang B Weddell G Loring J Kurahara C Dudley E.C Hayday A et al.EMBO J. 1993; 12: 4863-4875Crossref PubMed Scopus (176) Google Scholar, 99Takai T Li M Sylvestre D Clynes R Ravetch J.V Cell. 1994; 76: 519-529Abstract Full Text PDF PubMed Scopus (803) Google Scholar). One of the earliest detectable signaling events following FcγRIII ligation is increased tyrosine kinase activity (28Einspahr K.J Abraham R.T Binstadt B.A Uehara Y Leibson P.J Proc. Natl. Acad. Sci. USA. 1991; 88: 6279-6283Crossref PubMed Scopus (88) Google Scholar, 74O'Shea J.J Weissman A.M Kennedy I.C.S Ortaldo J.R Proc. Natl. Acad. Sci. USA. 1991; 88: 350-354Crossref PubMed Scopus (101) Google Scholar, 107Vivier E Morin P O'Brien C Druker B Schlossman S.F Anderson P J. Immunol. 1991; 146: 206-210PubMed Google Scholar). Indeed, pharmacological inhibition of this protein tyrosine kinase (PTK) activation blocks the development of ADCC (28Einspahr K.J Abraham R.T Binstadt B.A Uehara Y Leibson P.J Proc. Natl. Acad. Sci. USA. 1991; 88: 6279-6283Crossref PubMed Scopus (88) Google Scholar, 75O'Shea J.J McVicar D.W Kuhns D.B Ortaldo J.R J. Immunol. 1992; 148: 2497-2502PubMed Google Scholar). Two specific families of PTKs have been implicated in proximal signaling initiated by FcγRIII ligation: the Src-family PTKs (which in NK cells include Lck, Fyn, Yes, and Lyn) and the Syk-family PTKs (which in NK cells include ZAP-70 and Syk) (Figure 1). Lck is detectable in anti-FcγRIII immunoprecipitates, and crosslinking of the FcR increases the in vitro catalytic activity of Lck (27Cone J.C Lu Y Trevillyan J.M Bjorndahl J.M Phillips C.A Eur. J. Immunol. 1993; 23: 2488-2497Crossref PubMed Scopus (44) Google Scholar, 82Pignata C Prasad K.V.S Robertson M.J Levine H Rudd C.E Ritz J J. Immunol. 1993; 151: 6794-6800PubMed Google Scholar, 92Salcedo T.W Korosaki T Kanakaraj P Ravetch J.V Perussia B J. Exp. Med. 1993; 177: 1475-1480Crossref PubMed Scopus (107) Google Scholar). In addition, FcR stimulation in NK cells induces rapid tyrosine phosphorylation of both ZAP-70 and Syk (108Vivier E da Silva A.J Ackerly M Levine H Rudd C.E Anderson P Eur. J. Immunol. 1993; 23: 1872-1876Crossref PubMed Scopus (69) Google Scholar, 98Stahls A Liwszyc G.E Couture C Mustelin T Andersson L.C Eur. J. Immunol. 1994; 24: 2491-2496Crossref PubMed Scopus (40) Google Scholar). Similar to TCR-initiated signaling, Lck can play a regulatory role in the FcR-induced tyrosine phosphorylation and enhanced catalytic activity of Syk-family PTKs (101Ting A.T Dick C.J Schoon R.A Karnitz L.M Abraham R.T Liebson P.J J. Biol. Chem. 1995; 270: 16415-16421Crossref PubMed Scopus (89) Google Scholar). However, as noted earlier, FcR-initiated signaling does not require Lck or Fyn. This could be due to redundancy by other Src-family members, but investigations to date have not shown that other Src-family PTKs couple to the FcγRIIIA. Rather, recent findings obtained in other types of hematopoietic cells suggest that Syk (but not ZAP-70) has the potential to tyrosine phosphorylate ITAM-containing receptors and to initiate downstream activation in a Src-family–independent manner (25Chu D.H Spits H Peyron J.-F Rowley R.B Bolen J.B Weiss A EMBO J. 1996; 15: 6251-6261Crossref PubMed Scopus (108) Google Scholar, 77Pao L.I Cambier J.C J. Immunol. 1997; 158: 2663-2669PubMed Google Scholar, 115Zoller K.E MacNeil I.A Brugge J.S J. Immunol. 1997; 158: 1650-1659PubMed Google Scholar). These findings are also consistent with the observation that CD45, a critical regulator of Src-family PTKs, is not required for signaling initiated by multisubunit immune recognition receptors that are coupled to Syk (25Chu D.H Spits H Peyron J.-F Rowley R.B Bolen J.B Weiss A EMBO J. 1996; 15: 6251-6261Crossref PubMed Scopus (108) Google Scholar, 77Pao L.I Cambier J.C J. Immunol. 1997; 158: 2663-2669PubMed Google Scholar). Therefore, the potential for the ITAM-containing γ subunit of the FcR complex in human and murine NK cells to couple to Syk may account for its ability to mediate ADCC in the absence of Lck, Fyn, CD45, or ZAP-70. The FcR-initiated proximal activation of PTKs in NK cells modifies multiple downstream signaling elements that contribute to the development of ADCC and cytokine secretion (Figure 1). Both PLC-γ1 and PLC-γ2 are tyrosine phosphorylated following FcγRIII ligation (4Azzoni L Kamoun M Salcedo T.W Kanakaraj P Perussia B J. Exp. Med. 1992; 176: 1745-1750Crossref PubMed Scopus (100) Google Scholar, 100Ting A.T Karnitz L.M Schoon R.A Abraham R.T Leibson P.J J. Exp. Med. 1992; 176: 1751-1755Crossref PubMed Scopus (121) Google Scholar). Activated PLC-γ cleaves membrane phosphoinositides to generate inositol-1,4,5-trisphosphate and sn-1,2-diacylglycerol, resulting in increased intracellular free calcium concentration ([Ca2+]i) and protein kinase C, respectively. The elevated [Ca2+]i is required for the granule release involved in the delivery of the lethal hit. Another downstream effector that requires proximal PTK activation is PI3K. PI3K is a lipid kinase consisting of a p85 regulatory subunit and a p110 catalytic subunit, and FcγR crosslinking induces increased PI3K activity (42Kanakaraj P Duckwort B Azzoni L Kamoun M Cantley L.C Perussia B J. Exp. Med. 1994; 179: 551-558Crossref PubMed Scopus (84) Google Scholar). The critical role of PI3K in ADCC is highlighted by the demonstration that wortmannin, a fungal metabolite that inhibits PI3K by binding irreversibly to its p110 catalytic subunit, blocks FcR-initiated killing (10Bonnema J.D Karnitz L.M Schoon R.A Abraham R.T Leibson P.J J. Exp. Med. 1994; 180: 1427-1435Crossref PubMed Scopus (123) Google Scholar). FcR stimulation also induces the activation of Ras (associated with Shc and p36 tyrosine phosphorylation) (35Galandrini R Palmieri G Piccoli M Frati L Santoni A J. Exp. Med. 1996; 183: 179-186Crossref PubMed Scopus (41) Google Scholar), Vav (112Xu X Chong A.S.-F Biochem. J. 1996; 318: 527-532PubMed Google Scholar), PLA2, Erk-2 (61Milella M Gismondi A Roncaioli P Bisogno L Palmieri G Frati L Cifone M.G Santoni A J. Immunol. 1997; 158: 3148-3154PubMed Google Scholar), nuclear factor of activated T cells-p, and nuclear factor of activated T cells-c (3Aramburu J Azzoni L Rao A Perussia B J. Exp. Med. 1995; 182: 801-810Crossref PubMed Scopus (111) Google Scholar). These second messengers are believed to regulate cytoskeletal changes and transcriptional events following receptor ligation. “Natural cytotoxicity” refers to the capacity of NK cells to mediate antitumor or antiviral immunity without prior sensitization and in the absence of antibody. In contrast to the clear molecular definition of the receptor that initiates ADCC, attempts to identify a single triggering receptor for natural cytotoxicity have been unsuccessful. In fact, the emerging picture suggests that a variety of activating cellular receptors may influence the ability of NK cells to respond to cells and soluble mediators in their microenvironment (reviewed by48Lanier L.L Immunity. 1997; 6: 371-378Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar). A recurring theme in recent reports is that molecules traditionally thought of as “adhesion” or “costimulatory” receptors on other hematopoietic cell types may, alone or in concert with other cell surface molecules, trigger NK cell activation. These include a variety of integrins (e.g., α4β1, α5β1, LFA-1, and αvβ3) (37Gismondi A Milella M Palmieri G Piccoli M Frati L Santoni A J. Immunol. 1995; 154: 3128-3137PubMed Google Scholar, 83Rabinowich H Lin W.C Amoscato A Herberman R.B Whiteside T.L J. Immunol. 1995; 154: 1124-1135PubMed Google Scholar, 84Rabinowich H Maniculea M Herberman R.B Whiteside T.L Blood. 1995; 85: 1858-1864PubMed Google Scholar, 38Helander T.S Carpen O Turunen O Kovanen P.E Vaheri A Timonen T Nature. 1996; 382: 265-268Crossref PubMed Scopus (200) Google Scholar, 85Rabinowich H Maniculea M Herberman R.B Whiteside T.L J. Immunol. 1996; 157: 3860-3868PubMed Google Scholar), CD2 (96Siliciano R.F Pratt J.C Schmidt R.E Ritz J Reinherz E.L Nature. 1985; 317: 428-430Crossref PubMed Scopus (235) Google Scholar), CD44 (34Galandrini R DeMaria R Piccoli M Frati L Santoni A J. Immunol. 1994; 153: 4399-4407PubMed Google Scholar, 94Sconocchia G Titus J.A Segal D.M J. Immunol. 1994; 153: 5473-5481PubMed Google Scholar), and CD69 (64Moretta A Piggi A Pende D Tripodi G Orengo A.M Pella N Augugliaro R Bottino C Ciccone E Moretta L J. Exp. Med. 1991; 174: 1393-1398Crossref PubMed Scopus (182) Google Scholar). In addition, receptors such as NKR-P1 (22Chambers W.H Vujanovic N.L DeLeo A.B Olszowy M.W Herberman R.B Hiserodt J.C J. Exp. Med. 1989; 169: 1373-1389Crossref PubMed Scopus (382) Google Scholar, 91Ryan J.C Niemi E.C Nakamura M.C Seaman W.E J. Exp. Med. 1995; 181: 1911-1915Crossref PubMed Scopus (117) Google Scholar), DNAX accessory molecule-1 (95Shibuya A Campbell D Hannum C Yssel H Franz-Bacon K McClanahan T Kitamura T Nicholl J Sutherland G.R Lanier L.L et al.Immunity. 1996; 4: 573-581Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar), NK-TR (32Frey J.L Bino T Kantor R.R.S Segal D.M Giardina S.L Roder J Anderson S Ortaldo J.R J. Exp. Med. 1991; 174: 1527-1536Crossref PubMed Scopus (41) Google Scholar), and Lag3 (62Miyazaki T Dierich A Benoist C Mathis D Science. 1996; 272: 405-408Crossref PubMed Scopus (113) Google Scholar) have been implicated as contributors to the development of certain forms of NK cell–mediated killing. Finally, some NK cells express on their cell surface activating isoforms of human killer cell inhibitory receptors (KIR), human CD94/NKG2, and murine Ly49 (59Mason L.H Yagita H Ortaldo J.R J. Leuk. Biol. 1994; 55: 362-370PubMed Google Scholar, 65Moretta A Sivori S Vitale M Pende D Morel L Augugliaro R Bottino C Moretta L J. Exp. Med. 1995; 182: 875-884Crossref PubMed Scopus (429) Google Scholar, 80Perez-Villar J.J Melero I Rodriguez A Carretero M Aramburu J Sivori S Orengo A.M Moretta A Lopez-Botet M J. Immunol. 1995; 154: 5779-5788PubMed Google Scholar, 7Biassoni R Cantoni C Falco M Verdiani S Bottino C Vitale M Conte R Poggi A Moretta A Moretta L J. Exp. Med. 1996; 183: 645-650Crossref PubMed Scopus (300) Google Scholar, 11Bottino C Sivori S Vitale M Cantoni C Falco M Pende D Morel L Augugliaro R Semenzato G Biassoni R et al.Eur. J. Immunol. 1996; 26: 1816-1824Crossref PubMed Scopus (112) Google Scholar, 13Brumbaugh K.M Perez-Villar J.J Dick C.J Schoon R.A Lopez-Botet M Leibson P.J J. Immunol. 1996; 157: 2804-2812PubMed Google Scholar, 58Mandelboim O Davis D.M Reyburn H.T Vales-Gomez M Sheu E.G Pazmany L Strominger J.L Science. 1996; 274: 2097-2100Crossref PubMed Scopus (86) Google Scholar, 60Mason L.H Anderson S.K Yokoyama W.M Smith H.R.C Winkler-Pickett R Ortaldo J.R J. Exp. Med. 1996; 184: 2119-2128Crossref PubMed Scopus (183) Google Scholar, 20Carretero M Cantoni C Bellon T Bottino C Biassoni R Rodriguez A Perez-Villar J.J Moretta L Moretta A Lopez-Botet M Eur. J. Immunol. 1997; 27: 563-567Crossref PubMed Scopus (236) Google Scholar, 39Houchins J.P Lanier L.L Niemi E.C Phillips J.H Ryan J.C J. Immunol. 1997; 158: 3603-3609PubMed Google Scholar). These activating molecules differ from their MHC-recognizing inhibitory counterparts (discussed in the next section) by lacking inhibitory motifs in their short cytoplasmic domains and by potentially associating with additional subunits that may transduce activating signals to the cell interior. Whether these receptors participate in MHC recognition or contribute to natural cytotoxicity remains to be determined. Given the number of potential receptors involved in natural cytotoxicity, the killing of different targets is likely to be regulated at least in part by different second messengers. This heterogeneity must be kept in mind in the attempt to formulate generalizable conclusions. However, studies done to date have consistently demonstrated that PTK activation, PLC-catalyzed release of phosphoinositides, and elevations in [Ca2+]i are early and requisite events during the development of most forms of natural cytotoxicity (reviewed by14Brumbaugh K.M Binstadt B.A Leibson P.J Curr. Topics Microbiol. Immunol., in press. 1997; Google Scholar). The similarity of these signaling events with those used during FcγRIII-dependent killing invites speculation that ITAM-containing subunits coupled to specific proximal PTKs may also play a role in the development of natural cytotoxicity. If so, ζ and γ are not the ITAM-containing receptors, since NK cells lacking these subunits can mediate natural cytotoxicity (54Liu C.-P Ueda R She J Sancho J Wang B Weddell G Loring J Kurahara C Dudley E.C Hayday A et al.EMBO J. 1993; 12: 4863-4875Crossref PubMed Scopus (176) Google Scholar, 99Takai T Li M Sylvestre D Clynes R Ravetch J.V Cell. 1994; 76: 519-529Abstract Full Text PDF PubMed Scopus (803) Google Scholar). As is the case for ADCC, Lck and ZAP-70 are not required for natural killing (24Chen A.C Kadlecek T.A Elder M.E Filipovich A.H Kuo W.-L Iwashima M Parslow T.G Weiss A Science. 1994; 264: 1599-1601Crossref PubMed Scopus (412) Google Scholar, 68Negishi I Motoyama N Nakayama K.-I Nakayama K Senju S Hatakeyama S Zhang Q Chan A.C Loh D.Y Nature. 1995; 376: 435-438Crossref PubMed Scopus (456) Google Scholar, 111Wen T Zhang L Kung S.K Molina T.J Miller R.G Mak T.W Eur. J. Immunol. 1995; 25: 3155-3159Crossref PubMed Scopus (41) Google Scholar, 105van Oers N.S.C Lowin-Kropf B Finlay D Connolly K Weiss A Immunity. 1996; 5: 429-436Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). To date, no information is available as to whether Syk might play a key regulatory role in natural cytotoxicity. Parallels with FcR-initiated signaling are directly apparent in the killing initiated by activating forms of the receptors whose extracellular domains are homologous to the MHC-recognizing inhibitory receptors (i.e., KIR, Ly49, CD94/NKG2). For example, human killer cell activating receptors (KARs) have extracellular domains homologous to the immunoglobulin superfamily KIRs, but their short cytoplasmic tails do not contain the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that are responsible for KIR inhibitory function. Instead, KARs express a single lysine residue within their transmembrane domains, similar to the charged amino acid residue in the transmembrane portion of the ligand-binding subunits of multiple immune recognition receptor complexes (e.g., TCR αβ, FcγRIIIα, and FcεRIα). In each case, this residue is required for assembly with their ITAM-containing subunits. A set of disulfide-linked dimers have recently been biochemically identified in KAR immunoprecipitates, and the tyrosine phosphorylation of these KAR-associated polypeptides is presumed to initiate intracellular signaling (70Olcese L Cambiaggi A Semenzato G Bottino C Moretta A Vivier E J. Immunol. 1997; 158: 5083-5086PubMed Google Scholar). Similarly, the activating form of the C-type lectin CD94/NKG2 complex consists of a disulfide-linked heterodimer made up of a CD94 subunit (seven–amino acid cytoplasmic tail) and an NKG2 family member (e.g., NKG2-C) that lacks an ITIM (23Chang C Rodriguez A Carretero M Lopez-Botet M Phillips J.H Lanier L.L Eur. J. Immunol. 1995; 25: 2433-2437Crossref PubMed Scopus (187) Google Scholar, 52Lazetic S Chang C Houchins J.P Lanier L.L Phillips J.H J. Immunol. 1996; 157: 4741-4745PubMed Google Scholar, 20Carretero M Cantoni C Bellon T Bottino C Biassoni R Rodriguez A Perez-Villar J.J Moretta L Moretta A Lopez-Botet M Eur. J. Immunol. 1997; 27: 563-567Crossref PubMed Scopus (236) Google Scholar, 39Houchins J.P Lanier L.L Niemi E.C Phillips J.H Ryan J.C J. Immunol. 1997; 158: 3603-3609PubMed Google Scholar). To date, ITAM-containing associated subunits have not been identified for CD94/NKG2-C, but the signals derived from this receptor complex include proximal activation of PTKs (Lck, ZAP-70, and Syk) and PLC-γ, inositol phosphate release, and elevations in [Ca2+]i (80Perez-Villar J.J Melero I Rodriguez A Carretero M Aramburu J Sivori S Orengo A.M Moretta A Lopez-Botet M J. Immunol. 1995; 154: 5779-5788PubMed Google Scholar, 13Brumbaugh K.M Perez-Villar J.J Dick C.J Schoon R.A Lopez-Botet M Leibson P.J J. Immunol. 1996; 157: 2804-2812PubMed Google Scholar). The ITAM-containing ζ and γ subunits are not tyrosine-phosphorylated following CD94/NKG2-C ligation, suggesting the utilization of separate transducing subunits. Although there are striking similarities between the intracellular signaling events described above for natural cytotoxicity and those taking place during FcγRIII-initiated signaling, there are some signaling elements that are used differentially during natural killing compared with ADCC. For example, whereas natural cytotoxicity against prototypic NK-sensitive targets, such as K562, can be controlled by protein kinase C–dependent PI3K-independent pathways, FcR-initiated granule release and killing can be regulated by protein kinase C–independent PI3K-dependent pathways (10Bonnema J.D Karnitz L.M Schoon R.A Abraham R.T Leibson P.J J. Exp. Med. 1994; 180: 1427-1435Crossref PubMed Scopus (123) Google Scholar). In addition, as noted above, given the number of potential receptors involved in natural cytotoxicity, the killing of different targets is likely to elicit qualitatively or quantitatively different signals. For example, certain virus-infected and LAK (lymphokine-activated killer)–sensitive targets trigger NK cell-mediated killing in the absence of detectable PLC-dependent calcium signaling (114Zanovello P Roasato A Bronte V Cerundolo V Treves S Di Virgilio F Pozzan T Biasi G Collavo D J. Exp. Med. 1989; 170: 665-677Crossref PubMed Scopus (38) Google Scholar, 79Paya C.V Schoon R.A Leibson P.J J. Immunol. 1990; 144: 4370-4375PubMed Google Scholar). Additional progress in defining the relevant signals that critically regulate the development of natural cytotoxicity will depend on clear molecular identification of the involved triggering receptors. Although many studies to date have focused on defining the signaling events that induce NK cell activation, there is increasing agreement that the capacity of NK cells to mediate killing or to secrete cytokines is determined by a balance between positive and negative regulatory events. In particular, there has been broad interest in recent data showing that receptor-mediated recognition of MHC class I complexes on target cells can block NK cell and T cell cytotoxic function in vitro and in vivo. The inhibitory MHC-recognizing receptors defined thus far include human KIR (two or three immunoglobulin superfamily domains in their extracellular regions), human CD94/NKG2 (both subunits are members of the C-type lectin superfamily), and murine Ly49 (type II disulfide-linked dimeric integral membrane proteins with homology to the C-type lectin superfamily) (Figure 2) (reviewed by12Brown M.G Scalzo A.A Matsumoto K Yokoyama W.M Immunol. Rev. 1997; 155: 53-65Crossref PubMed Scopus (146) Google Scholar, 26Colonna M Immunol. Rev. 1997; 155: 127-133Crossref PubMed Scopus (104) Google Scholar, 48Lanier L.L Immunity. 1997; 6: 371-378Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, 56Long E.O Wagtmann N Curr. Opin. Immunol., in press. 1997; Google Scholar). Different MHC-recognizing receptors have differing specificities for distinct families of MHC class I molecules, and clonal subpopulations of NK cells differ in their expression of specific MHC-recognizing receptors. When tumor cells or virus-infected cells have down-regulated their surface class I expression, they potentially enhance their susceptibility to NK cell-mediated killing (43Karre K Ljunggren H.G Piontek G Kiessling R Nature. 1986; 319: 675-678Crossref PubMed Scopus (1597) Google Scholar, 44Kaufman D.S Schoon R.A Leibson P.J Proc. Natl. Acad. Sci. USA. 1992; 89: 8337-8341Crossref PubMed Scopus (49) Google Scholar, 31Farrell H.E Vally H Lynch D.M Fleming P Shellam G.R Scalzo A.A Davis-Poynter N.J Nature. 1997; 386: 510-514Crossref PubMed Scopus (237) Google Scholar, 90Reyburn H.T Mandelboim O Vales-Gomez M Davis D.M Pazmany L Storminger J.L Nature. 1997; 386: 514-517Crossref PubMed Scopus (241) Google Scholar). However, it should be emphasized that certain targets with decreased MHC class I are not sensitive to NK cytotoxicity, suggesting that the removal of inhibitory signals without concurrent recognition of a triggering epitope may be insufficient to initiate NK cellular activation. Conversely, certain targets are such potent activators of NK cells that MHC expression does not inhibit their killing (51Lanier L.L Corliss B Phillips J.H Immunol. Rev. 1997; 155: 145-154Crossref PubMed Scopus (215) Google Scholar). Despite the structural heterogeneity in the extracellular, MHC-recognizing portion of the various inhibitory receptors, emerging evidence suggests that a common inhibitory mechanism may be used in each case (9Binstadt B.A Brumbaugh K.M Leibson P.J Immunol. Rev. 1997; 155: 197-203Crossref PubMed Scopus (39) Google Scholar, 88Renard V Cambiaggi A Vely F Blery M Olcese L Olivero S Bouchet M Vivier E Immunol. Rev. 1997; 155: 205-221Crossref PubMed Scopus (103) Google Scholar). This mechanism includes (1) ty" @default.
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• W2021406365 date "1997-06-01" @default.
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• W2021406365 title "Signal Transduction during Natural Killer Cell Activation: Inside the Mind of a Killer" @default.
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• W2021406365 doi "https://doi.org/10.1016/s1074-7613(00)80441-0" @default.
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