- Email: [email protected]
The dialogue between human natural killer cells and dendritic cells
The dialogue between human natural killer cells and dendritic cells Alessandro Moretta The interaction of NK cells with dendritic cells (DCs) appears to play an important role in both innate and adaptive immune responses to pathogens. In peripheral inflamed tissues the simultaneous engagement of receptors for danger (e.g. Toll-like receptors), which are expressed by both NK cells and DCs, results in cell activation and the acquisition of functional properties necessary for controlling, and possibly rapidly eliminating, pathogens by innate effector mechanisms. Moreover, NK cells are needed to select the most appropriate DCs that display the functional properties suitable for subsequent T-cell priming. This NK-cell-mediated programming of DC maturation is modulated by cytokines released during the early stages of inflammatory responses (i.e. IL-12, IFN-g, IL-4). NK cells and DCs continue their interactions in secondary lymphoid organs where both cell types play a role in the control of T-cell priming. Addresses Dipartimento di Medicina Sperimentale, Universita` degli Studi di Genova, Via LB Alberti 2, 16132 Italy Corresponding author: Moretta, Alessandro ([email protected])
Current Opinion in Immunology 2005, 17:306–311 This review comes from a themed issue on Lymphocyte effector functions Edited by Lorenzo Moretta Available online 11th April 2005 0952-7915/$ – see front matter # 2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2005.03.004
Introduction The effector function of NK cells is regulated by a balance between opposite signals delivered by a set of MHC class-I-specific inhibitory receptors and by several activating receptors and co-receptors responsible for NK cell triggering. By the combined use of these receptors, NK cells can discriminate between normal MHC class I positive (MHC-class I+) cells and cells that have lost the expression of MHC class I molecules as a consequence of tumour transformation or viral infection [1]. It has become evident in recent years, however, that the actual role of NK cells is not confined to the destruction of virus-infected cells or tumours [2,3]. Indeed, NK cells can interact with other innate immune cells that are present during the early phases of inflammatory responses. These Current Opinion in Immunology 2005, 17:306–311
interactions can result in shaping both the innate immune response within inflamed peripheral tissues and the adaptive immune response in secondary lymphoid organs. An interesting example of the interactions between NK cells and other innate immune cells is the so-called ‘NK–DC cross-talk’ which follows the recruitment of both NK cells and DCs to sites of inflammation in response to infection [4–6]. Following priming by pathogen-derived products, the reciprocal NK–DC interactions result in potent activating bi-directional signalling, which regulates both the quality and the intensity of innate immune responses. Thus, pathogen-primed NK cells in the presence of cytokines released by DCs become activated. In turn, activated NK cells release other cytokines that favour DC maturation and select the most suitable DCs for subsequent migration to lymph nodes and efficient T-cell priming. In addition, a specialized subset of NK cells can be recruited directly to the lymph nodes to participate in the process of T-cell priming via the release of IFN-g. Here, I will briefly summarize the most relevant recent findings supporting the notion that interactions between NK cells and DCs are likely to play a crucial role not only in shaping innate immune responses but also in the editing process that precedes the priming phase of adaptive responses.
The human NK-cell receptors that are involved in target cell killing It is a common notion that the inhibitory effect mediated by MHC class-I-specific receptors on NK-cell function protects normal cells from the attack of autologous NK cells, while rendering cells with compromised MHC class I expression (e.g. following tumour transformation or viral infection) susceptible to NK-cell-mediated killing [7–10]. In humans, two main families of HLA-class I-specific inhibitory surface receptors have been identified; those belonging to the immunoglobulin superfamily termed killer immunoglobulin-like receptors (KIRs), which are specific for allelic determinants expressed by groups of HLA-A, -B or -C allotypes, and the CD94–NKG2A heterodimer (related to the C-type lectins), which is specific for the non-classical HLA class I molecule HLA-E. A series of triggering receptors are implicated in NK-cell activation, resulting in natural cytotoxicity. Among these, expression of the so called ‘natural cytotoxicity receptors’ (NCRs), which include NKp46, NKp30 and NKp44, is www.sciencedirect.com
The dialogue between human NK cells and DCs Moretta 307
restricted to NK cells and are thus the most reliable markers for human NK-cell identification [11]. Another surface receptor that plays a relevant role in NK-cellmediated cytolysis of tumours is NKG2D, which is also expressed by most cytolytic T cells and is specific for the stress-inducible MICA/B or UL16 binding proteins (ULBPs) [12,13]. Other triggering surface molecules expressed by NK cells appear to function primarily as co-receptors, as their ability to signal seems to depend on the simultaneous co-engagement of NCR or NKG2D. These surface molecules include 2B4, NTB-A, NKp80, CD59 [14] and CD226 [15]. The majority of the cellular ligands recognized by the various activating receptors and co-receptors (including those recognized by NCRs) remain undefined [16]. The only exceptions are represented by the ligands of NKG2D, as mentioned above, by CD48, which binds 2B4, and by NTB-A, which has been demonstrated to mediate homotypic interactions [17,18]. The ligands recognized by DNAM-1 have recently been identified [19] as the poliovirus receptor (PVR; also called CD155) and Nectin-2 (CD112), two members of the nectin family, which are also involved in cell–cell adhesion and in leukocyte extravasation [20]. Remarkably, both PVR and Nectin-2 can be overexpressed on tumour cells of different histotypes [19]. The recognition of selfligands that are expressed or overexpressed upon tumour transformation or viral-infection might be a general strategy to focus NK cells on target cells that should be promptly destroyed.
NK cells have receptors for pathogenassociated molecular patterns An alternative mode of NK-cell activation has recently been identified thanks to the discovery that human NK cells can express Toll-like receptors (TLRs) [21,22,23]. TLRs are pattern recognition receptors (PRRs), which trigger innate immune responses, providing both immediate protection against various pathogens and instructing the adaptive immune system through the induction of DC recruitment and maturation [24]. Ten different TLRs have been described in humans, and most of their specific ligands have been identified. The targets of PRRs are the pathogen-associated molecular patterns (PAMPs). These include lipopolysaccharide (LPS) of gram bacteria, which is recognized by TLR4; bacterial lipoproteins and lipoteichoic acids, which are recognized by TLR2; flagellin (recognised by TLR5); unmethylated CpG typical of bacterial and viral DNA (recognised by TLR9); and double-stranded RNA (dsRNA; recognised by TLR3) as well as single-stranded RNA (recognised by TLR7). As recently shown by Sivori et al. [21], human NK cells, independent of their status of activation, express functional TLR3 and TLR9 (although they do not seem to express other TLRs), thus enabling their response to both viral and bacterial products. In particular, dsRNA or CpG www.sciencedirect.com
can induce NK-cell priming, which, in the presence of IL-12 secreted by myeloid DCs, results in the release of abundant IFN-g and TNF-a. Moreover, under these conditions, NK cells upregulate their cytolytic activity against tumour cells and acquire the ability to kill immature myeloid DCs (iDCs) [21]. Thus, the simultaneous engagement of TLR3 expressed by both NK cells and myeloid DC might be sufficient to initiate the series of events characterizing the early phases of innate immune responses. Little is known so far regarding the possible cross-talk between human NK cells and plasmacytoid DCs (PDCs). However, as both NK cells and DCs express TLR9, it is conceivable that CpG can prime both cell types. The abundant release of type I IFN [25], a potent inducer of NK cell cytotoxicity, by PDCs suggests that NK–PDC interactions can result in enhanced anti-viral innate protection. After their recruitment to inflamed tissues, NK cells and myeloid iDCs start their dialogue by getting into close physical contact [26–28]. The formation of stimulatory synapses between the two cell types promotes the polarized secretion of IL-12, which is present in preassembled stores in DCs, towards NK cells [29]. This close cell–cell interaction appears to be required for promoting a series of events, including DC-induced NK-cell proliferation, NK-cell-mediated killing of iDCs, NK-cellmediated cytokine release and NK-cell-dependent DC maturation [4,5].
NK cell–dendritic cell interactions at inflammatory sites: impact on downstream T-cell polarisation Pathogen-induced inflammatory responses in peripheral tissues are characterized by the release of various cytokines and chemokines by resident DCs and by other cell types including endothelial cells, macrophages, neutrophils, fibroblasts, mast cells and eosinophils. Some of these factors favour the extravasation of NK cells and their subsequent priming. Indeed, the majority of circulating NK cells, characterized by the CD56+CD16+ surface phenotype, express chemokine receptors, such as CXCR1 and CX3CR1, which bind CXCL8, CCL3 and CX3CL1 [4]. Moreover, myeloid DCs that are undergoing maturation upon antigen uptake release cytokines including IL-12 and IL-15, which deeply affect the functional behaviour of primed NK cells. Indeed, IL-12 is crucial for the induction of IFN-g release by NK cells as well as for the enhancement of NK-cell cytotoxicity [3,30], whereas a membrane-bound form of IL-15 appears to play a role in the induction of NK-cell proliferation [31]. Certain types of myeloid DCs, such as Langerhans cells (LCs), do not secrete bioactive IL-12p70 but they do produce high levels of IL-15 and IL-18. LCs, however, do not induce NK-cell activation, as they lack the IL-15Ra, which is Current Opinion in Immunology 2005, 17:306–311
308 Lymphocyte effector functions
required for surface anchoring of IL-15 and presentation to NK cells [32]. During the early phases of inflammatory responses, however, the engagement of TLRs might also result in the activation of other cell types involved in innate immune responses. These include resident mast cells [33] or eosinophils [34,35], which, through the release of cytokines other than IL-12 (e.g. IL-4), can deviate the subsequent adaptive response towards a state of tolerization or towards the generation of either Th2 or unpolarized T cells [36,37]. Along this line, although short-term NK-cell exposure to IL-12 promotes the release of high levels of both IFN-g and TNF-a as well as the acquisition of cytolytic activity, exposure to IL-4 results in little cytokine production and lack of cytolytic activity. Moreover, only IL-12-exposed NK cells can promote efficient DC maturation [36]. These data suggest that IL-12-primed NK cells can contribute to the selection of mature myeloid DCs (mDCs) that are capable of optimally priming Th1 responses. On the contrary, however, NK-cell priming with IL-4 might result in abnormal DC maturation characterized by both qualitative and quantitative alterations, which could eventually result in either Th2 or tolerogenic responses [36,37].
number of iDCs available for generating suitable numbers of mDCs. Accordingly, as recently suggested, the lack of NK-cell-mediated DC killing could result in altered numbers of DCs reaching complete maturation [4,40]. Thus, depending on the type of cytokines (type I or type II) released during the early stages of an inflammatory response, by either resident or recruited cells, NK cells differentially contribute to the quality and magnitude of innate immune responses. This, in turn, is likely to impact on the subsequent adaptive immune responses, as recently suggested by several studies [36,37,41–43].
NK cells in lymph nodes
A remarkable event that can occur during NK–DC interactions is the NK-cell-mediated killing of autologous myeloid iDCs. This event is dependent on a process of NK-cell activation involving NKp30 and its still undefined ligand expressed on DCs [27]. NK-mediated DC killing is inhibited by TGF-b, as this cytokine profoundly downregulates surface expression of NKp30 [38]; however, only a fraction of peripheral blood NK cells are capable of killing autologous iDCs. This NK-cell subset does not express inhibitory KIRs specific for self-HLA class I alleles but does express the CD94–NKG2A inhibitory HLA-E-specific receptor [39]. The explanation of why only this particular subset mediates myeloid iDC killing is that these cells display a sharp downregulation of surface HLA class I molecules, which primarily affects HLA-E.
Within normal non-inflamed lymph nodes NK cells are localized in the para-follicular area next to the paracortical T-cell area [44,45]. These NK cells are homogeneously characterized by the CD56bright, CD94– NKG2A+ surface phenotype, by low levels of cytolytic activity and by the production of large amounts of IFN-g. These cells are similar to the small CD56bright CD16– NK-cell subset present in peripheral blood which accounts for approximately 10% of the total circulating NK-cell pool [30]. This peripheral blood NK-cell subset is capable of substantial proliferation in the presence of LPS-activated myeloid iDCs [46] and constitutively expresses the CCR7+ CD62Lhigh surface phenotype required for migration to secondary lymphoid compartments (SLCs). In this context, however, recent studies in mice indicated that NK cells can also be recruited in a CCR7-independent, CXCR3-dependent manner into antigen-stimulated lymph nodes. At this site, they provide an early source of IFN-g necessary for Th1 polarization [42]. Interestingly, and in contrast to the human peripheral blood CD56bright CD16– NK cell subset, which expresses very high levels of NCR (particularly NKp46) [46], the corresponding NK cells derived from SLC have virtually undetectable NKp46 and NKp30 [44,45]. This suggests that receptors undergo internalization following interaction with ligands expressed within the SLC. Remarkably, the surface expression of both NKp46 and NKp30 in SLC-derived NK cells can be upregulated by IL-2 [45].
Remarkably, NK cells can also influence the progression of DC maturation via the release of TNF-a, IFN-g and GM-CSF [26]. Moreover, additional factors, including necrotic material and heat-shock proteins generated during the NK-mediated killing of tumours, virus-infected cells or iDCs themselves, might play a role in inducing DC maturation [4,5]. It is of note that danger signals that promote the release of IL-12 by myeloid DCs also induce NK cells to initiate their editing program towards DCs. This is based on the capability of NK cells to kill myeloid DCs that underexpress HLA-class I molecules, a phenomenon that might keep in check the quality of DCs undergoing maturation and control the amplitude of DC responses. By this method, NK cells could limit the
In the SLC, a possible source of IL-2 is the antigenstimulated T cells (primed by their interaction with mDCs). In line with this concept, the combined action of IL-2 (T-cell derived) and IL-12 (DC derived) is sufficient to enable SLC NK cells to produce IFN-g [44]. Thus, one might speculate that primed T cells, soon after being primed by mDCs, release IL-2 which, in turn, would induce upregulation of NCRs in SLC NK cells (which constitutively express high-affinity IL-2 receptors). As a result, they become susceptible to activation (possibly by ligands expressed on primed [activated] T cells [11]) and start to release IFN-g. At this stage, the process could go on, even in the absence of IL-12. Indeed, this cytokine is released only for a short period of time
NK-cell-mediated selection of mature myeloid dendritic cells
Current Opinion in Immunology 2005, 17:306–311
www.sciencedirect.com
The dialogue between human NK cells and DCs Moretta 309
after the generation of mDCs (DC exhaustion) [47]. Additional cytokines, particularly IL-15, might also play a role in regulating NK-cell function within SLC. For example, mature myeloid DCs (CD83+) produce IL-15 in response to either phagocytic signals or type I IFN [48,49], whereas a membrane-bound form of IL-15 expressed by myeloid DCs can induce proliferation and survival of NK cells both in the periphery and in SLC [31].
Scientifica e Tecnologica (MIUR) and the European Union FP6, LSHB-CT-2004-503319-AlloStem. Also the financial support of Fondazione Compagnia di San Paolo, Torino, Italy, is gratefully acknowledged. I am also grateful to L Moretta for helpful discussion and for critical reading of this manuscript.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1.
Moretta A, Bottino C, Mingari MC, Biassoni R, Moretta L: What is a natural killer cell? Nat Immunol 2002, 3:6-8.
2.
Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002, 20:197-216.
3.
Biron CA: Activation and function of natural killer cell responses during viral infections. Curr Opin Immunol 1997, 9:24-34.
4.
Moretta A: Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2002, 2:957-965.
5.
Zitvogel L: Dendritic and Natural Killer Cells Cooperate in the Control/Switch of Innate Immunity. J Exp Med 2002, 195:F9-F14.
6.
Ferlazzo G, Munz C: NK cell compartements and their activation by dendritic cells. J Immunol 2004, 172:1333-1339.
7.
Moretta A, Bottino C, Vitale M, Pende D, Biassoni R, Mingari MC, Moretta L: Receptors for HLA-class I molecules in human Natural Killer cells. Annu Rev Immunol 1996, 14:619-648.
8.
Long EO: Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 1999, 17:875-904.
9.
Lopez-Botet M, Llano M, Navarro F, Bellon T: NK cell recognition of non-classical HLA class I molecules. Semin Immunol 2000, 12:109-119.
Concluding remarks Cellular interactions that occur between cells of the innate immune response have acquired increasing interest, not only with regard to the regulatory/potentiating mechanisms within innate immune responses but also because they can influence subsequent adaptive immune responses. The recent discovery that NK cells can respond to pathogen-derived products through TLRs opened a new avenue in our understanding of the general role of these cells in defence against infections. Infectious agents are known to exert the greatest selective pressure on our defensive mechanisms. Accordingly, it is not surprising that NK cells, thought to play a major role in the control of viral infections, can be also be alerted by bacterial and fungal products. Another concept that starts to emerge is that early signals delivered by cells of the innate immune system as a consequence of pathogen encounter, can shape the subsequent adaptive immunity by eliciting Th1 or Th2 responses. Thus, the type of response could reside well upstream of the DC–T helper cell interaction, and could involve cells of the innate immune system, including NK cells. A better understanding of these phenomena will help to design novel immunization protocols aimed at obtaining the most appropriate adaptive immune response. This goal could be achieved by delivering appropriate stimuli to cells of the innate immune system. One of the possible targets of such adoptive immunointervention might be the use of experimental procedures acting on the editing process by which NK cells are selecting the appropriate number and quality of DCs undergoing maturation. For example, potentiation of NK cell-mediated cytotoxicity against DCs may be capable of providing a powerful feedback mechanism to limit the excess of antigen presentation in SLCs and consequent overinflammation. In addition, the clearance of iDCs might prevent the generation of IL-10-producing regulatory T cells that may suppress both the priming and the effector phase of T cells responding against a given pathogen.
Acknowledgements This work was supported by grants awarded by Associazione Italiana per la Ricerca sul Cancro (AIRC), Istituto Superiore di Sanita` (ISS) and Ministero della Sanita`, Ministero dell’Universita` e della Ricerca www.sciencedirect.com
10. Vilches C, Parham P: KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 2002, 20:217-251. 11. Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, Biassoni R, Moretta L: Activating receptors and co-receptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 2001, 19:197-223. 12. Cerwenka A, Lanier LL: Ligands for natural killer cell receptors: redundancy or specificity. Immunol Rev 2001, 181:158-169. 13. Raulet DH: Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 2003, 3:781-790. 14. Marcenaro E, Augugliaro R, Falco M, Castriconi R, Parolini S, Sivori S, Romeo E, Millo R, Moretta L, Bottino C, Moretta A: CD59 is physically and functionally associated with natural cytotoxicity receptors and activates human NK cell-mediated cytotoxicity. Eur J Immunol 2003, 33:3367-3376. 15. Shibuya A, Campbell D, Hannum C, Yssel H, Franz-Bacon K, McClanahan T, Kitamura T, Nicholl J, Sutherland GR, Lanier LL, Phillips JH: DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 1996, 4:573-581. 16. Bottino C, Castriconi R, Moretta L, Moretta A: Cellular ligands for activating NK receptors. Trends Immunol 2005, in press. A timely overview on what is presently known on activating NK receptor– ligand interactions. 17. Falco M, Marcenaro E, Romeo E, Bellora F, Marras D, Vely F, Ferracci G, Moretta L, Moretta A, Bottino C: Homophilic interaction of NTBA, a member of the CD2 molecular family: induction of cytotoxicity and cytokine release in human NK cells. Eur J Immunol 2004, 34:1663-1672. 18. Flaig RM, Stark S, Waltzl C: Cutting edge: NTB-A activates NK cells via homophilic interaction. J Immunol 2004, 172:6524-6527. 19. Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B, Cantoni C, Grassi J, Marcenaro S, Reymond N Current Opinion in Immunology 2005, 17:306–311
310 Lymphocyte effector functions
et al.: Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 2003, 198:557-567. This study demonstrates that DNAM-1 can function as an activating NK receptor and identifies its ligands as the two nectins PVR and Nectin-2. Human NK cells, via DNAM-1, recognize and become activated by nectins expressed on tumour cells of different histotypes. 20. Reymond N, Imbert AM, Devilard E, Fabre S, Chabannon C, Xerri L, Farnarier C, Cantoni C, Bottino C, Moretta A, Dubreuil P, Lopez M: DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J Exp Med 2004, 199:1331-1341. This study is a logical follow-up of the previous one [19]. It identifies the interaction between DNAM-1 and PVR as a crucial event in monocyte migration through endothelial junctions. 21. Sivori S, Falco M, Della Chiesa M, Carlomagno S, Vitale M, Moretta L, Moretta A: CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumours and dendritic cells. Proc Natl Acad Sci USA 2004, 101:10116-10121. This paper demonstrates that human NK cells express Toll-like receptors 3 and 9 when exposed to DC-derived IL-12. Upon interaction with their ligands they activate NK cells by inducing both cytolytic activity and cytokine production. 22. Schmidt KS, Leung B, Kwong M, Zarember KA, Satyal S, Navas TA, Wang F, Godowski PJ: APC-independent activation of NK cells by the Toll-like receptor 3 agonist double-stranded RNA. J Immunol 2004, 172:138-143. This study, in line with the previous one [21], shows a TLR3-dependent, direct NK-cell activation. 23. Pisegna S, Pirozzi G, Piccoli M, Frati L, Santoni A, Palmieri G: p38 MAPK activation controls the TLR3-mediated upregulation of cytotoxicity and cytokine production in human NK cells. Blood 2004, 104:4157-4164. This paper, similar to the previous one [22], describes the TLR3-dependent NK-cell activation. The role of p38 MAPK in the activation process is also demonstrated. 24. Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 2004, 4:499-511.
33. Supajatura V, Ushio H, Nakao A, Akira S, Okumura K, Ra C, Ogawa H: Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity. J Clin Invest 2002, 109:1351-1359. 34. Nagase H, Okugawa S, Ota Y, Yamaguchi M, Tomizawa H, Matsushima K, Ohta K, Yamamoto K, Hirai K: Expression and function of Toll-like receptors in eosinophils: activation by Toll-like receptor 7 ligand. J Immunol 2003, 171:3977-3982. 35. Bjerke T, Gaustadnes M, Nielsen S, Nielsen LP, Schiotz PO, Rudiger N, Reimert CM, Dahl R, Christensen I, Poulsen LK: Human blood eosinophils produce and secrete interleukin 4. Respir Med 1996, 90:271-277. 36. Marcenaro E, Della Chiesa M, Bellora F, Parolini S, Millo R, Moretta L, Moretta A: IL12 or IL4 prime human Natural Killer cells to mediate functionally divergent interactions with dendritic cells or tumours. J Immunol 2005, 174:3992-3998. This study shows that the exposure of NK cells to distinct cytokine milieu during the early stages of inflammation has an important impact on the subsequent ability of NK cells to promote the editing program of myeloid DCs towards the generation of Th1 responses. 37. Della Chiesa M, Sivori S, Castriconi R, Marcenaro E, Moretta A: Pathogen induced-private conversations between natural killer and dendritic cells. Trends Microbiol 2005, 13:128-136. A review tracing the interactions between NK and DC in the context of pathogen infections. 38. Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A: TGFb1 inhibits expression of the NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci USA 2003, 100:4120-4125. 39. Della Chiesa M, Vitale M, Carlomagno S, Ferlazzo G, Moretta L, Moretta A: The Natural Killer Cell mediated killing of autologous dendritic cells is confined to a cell subset expressing CD94/NKG2A, but lacking inhibitory killer IG-like receptors. Eur J Immunol 2003, 33:1657-1666. This study identifies NKG2A+ KIR– cells as the human NK cell subset that displays cytolytic activity against immature DCs. The article also shows that killing is due to downregulation of surface HLA-E on DCs.
25. Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A, Colonna M: Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 1999, 5:919-923.
40. Cooper MA, Fehniger TA, Fuchs A, Colonna M, Caligiuri MA: NK cell and DC interactions. Trends Immunol 2004, 25:47-52. A timely review on the interactions between NK cells and DCs.
26. Piccioli D, Sbrana S, Melandri E, Valiante NM: Contactdependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 2002, 195:335-341.
41. Mailliard RB, Son YI, Redlinger R, Coates PT, Giermasz A, Morel PA, Storkus WJ, Kalinski P: Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function. J Immunol 2003, 171:2366-2373.
27. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C: Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 2002, 195:343-351. 28. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G: Reciprocal activating interaction between NK cells and dendritic cells. J Exp Med 2002, 195:327-333. 29. Borg C, Jalil A, Laderach D, Maruyama K, Wakasugi H, Charrier S, Ryffel B, Cambi A, Figdor C, Vainchenker W et al.: NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs. Blood 2004, 104:3267-3275. 30. Cooper MA, Fehniger TA, Caligiuri MA: The biology of human natural killer-cell subsets. Trends Immunol 2001, 22:633-640. 31. Ferlazzo G, Pack M, Thomas D, Paludan C, Schmid D, Strowig T, Bougras G, Muller WA, Moretta L, Munz C: Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc Natl Acad Sci USA 2004, 101:16606-16611. This study demonstrates a role for IL-15 bound to the surface of myeloid DCs that are in the process of inducting both NK-cell proliferation and survival. 32. Munz C, Dao T, Ferlazzo G, de Cos MA, Goodman K, Young JW: Mature myeloid dendritic cell subsets have distinct roles for activation and viability of circulating human natural killer cells. Blood 2005, 105:266-273. Current Opinion in Immunology 2005, 17:306–311
42. Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, Sallusto F: Induced recruitment of NK cells to lymph nodes provides IFN-g for Th1 priming. Nat Immunol 2004, 5:1260-1265. This outstanding study shows that NK cells can be recruited to lymph nodes by CCR7-independent mechanisms and that, by releasing IFNg, they play a crucial role in the early phases of T-cell priming. 43. Byrne P, McGuirk P, Todryk S, Mills KHG: Depletion of NK cells results in disseminating lethal infection with Bordetella pertussis associated with a reduction of antigen-specific Th1 and enhancement of Th2, but not Tr1. Eur J Immunol 2004, 34:2579. 44. Fehniger TA, Cooper MA, Nuovo GJ, Cella M, Facchetti F, Colonna M, Caligiuri MA: CD56bright natural killer cells are present in human lymph nodes and are activated by T cellderived IL-2: a potential new link between adaptive and innate immunity. Blood 2003, 101:3052-3057. This paper analyzes the distribution, phenotype and function of human NK cells that populate secondary lymphoid tissues. 45. Ferlazzo G, Thomas D, Lin SL, Goodman K, Morandi B, Muller WA, Moretta A, Munz C: The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell ig-like receptors and become cytolytic. J Immunol 2004, 172:1455-1462. This paper, similar to [44], analyzes NK cells in secondary lymphoid organs. It also provides evidence that these cells might de novo acquire KIRs at their surface. www.sciencedirect.com
The dialogue between human NK cells and DCs Moretta 311
46. Vitale M, Della Chiesa M, Carlomagno S, Romagnani C, Thiel A, Moretta L, Moretta A: The small subset of CD56brightCD16natural killer cells is selectively responsible for both cell proliferation andinterferon-gammaproduction uponinteraction with dendritic cells. Eur J Immunol 2004, 34:1715-1722. This study shows that both NK cell proliferation and production of IFN-g upon interaction with DCs are confined to the small NK subset expressing high surface densities of CD56 and lacking CD16. 47. Langenkamp A, Messi M, Lanzavecchia A, Sallusto F: Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat Immunol 2000, 1:311-316.
www.sciencedirect.com
48. Jonuleit H, Wiedemann K, Muller G, Degwert J, Hoppe U, Knop J, Enk AH: Induction of IL-15 messenger RNA and protein in human blood-derived dendritic cells: a role for IL-15 in attraction of T cells. J Immunol 1997, 158:2610-2615. 49. Jinushi M, Takehara T, Tatsumi T, Kanto T, Groh V, Spies T, Suzuki T, Miyagi T, Hayashi N: Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection. J Immunol 2003, 171:5423-5429.
Current Opinion in Immunology 2005, 17:306–311
Current Opinion in Immunology 2005, 17:306–311 This review comes from a themed issue on Lymphocyte effector functions Edited by Lorenzo Moretta Available online 11th April 2005 0952-7915/$ – see front matter # 2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2005.03.004
Introduction The effector function of NK cells is regulated by a balance between opposite signals delivered by a set of MHC class-I-specific inhibitory receptors and by several activating receptors and co-receptors responsible for NK cell triggering. By the combined use of these receptors, NK cells can discriminate between normal MHC class I positive (MHC-class I+) cells and cells that have lost the expression of MHC class I molecules as a consequence of tumour transformation or viral infection [1]. It has become evident in recent years, however, that the actual role of NK cells is not confined to the destruction of virus-infected cells or tumours [2,3]. Indeed, NK cells can interact with other innate immune cells that are present during the early phases of inflammatory responses. These Current Opinion in Immunology 2005, 17:306–311
interactions can result in shaping both the innate immune response within inflamed peripheral tissues and the adaptive immune response in secondary lymphoid organs. An interesting example of the interactions between NK cells and other innate immune cells is the so-called ‘NK–DC cross-talk’ which follows the recruitment of both NK cells and DCs to sites of inflammation in response to infection [4–6]. Following priming by pathogen-derived products, the reciprocal NK–DC interactions result in potent activating bi-directional signalling, which regulates both the quality and the intensity of innate immune responses. Thus, pathogen-primed NK cells in the presence of cytokines released by DCs become activated. In turn, activated NK cells release other cytokines that favour DC maturation and select the most suitable DCs for subsequent migration to lymph nodes and efficient T-cell priming. In addition, a specialized subset of NK cells can be recruited directly to the lymph nodes to participate in the process of T-cell priming via the release of IFN-g. Here, I will briefly summarize the most relevant recent findings supporting the notion that interactions between NK cells and DCs are likely to play a crucial role not only in shaping innate immune responses but also in the editing process that precedes the priming phase of adaptive responses.
The human NK-cell receptors that are involved in target cell killing It is a common notion that the inhibitory effect mediated by MHC class-I-specific receptors on NK-cell function protects normal cells from the attack of autologous NK cells, while rendering cells with compromised MHC class I expression (e.g. following tumour transformation or viral infection) susceptible to NK-cell-mediated killing [7–10]. In humans, two main families of HLA-class I-specific inhibitory surface receptors have been identified; those belonging to the immunoglobulin superfamily termed killer immunoglobulin-like receptors (KIRs), which are specific for allelic determinants expressed by groups of HLA-A, -B or -C allotypes, and the CD94–NKG2A heterodimer (related to the C-type lectins), which is specific for the non-classical HLA class I molecule HLA-E. A series of triggering receptors are implicated in NK-cell activation, resulting in natural cytotoxicity. Among these, expression of the so called ‘natural cytotoxicity receptors’ (NCRs), which include NKp46, NKp30 and NKp44, is www.sciencedirect.com
The dialogue between human NK cells and DCs Moretta 307
restricted to NK cells and are thus the most reliable markers for human NK-cell identification [11]. Another surface receptor that plays a relevant role in NK-cellmediated cytolysis of tumours is NKG2D, which is also expressed by most cytolytic T cells and is specific for the stress-inducible MICA/B or UL16 binding proteins (ULBPs) [12,13]. Other triggering surface molecules expressed by NK cells appear to function primarily as co-receptors, as their ability to signal seems to depend on the simultaneous co-engagement of NCR or NKG2D. These surface molecules include 2B4, NTB-A, NKp80, CD59 [14] and CD226 [15]. The majority of the cellular ligands recognized by the various activating receptors and co-receptors (including those recognized by NCRs) remain undefined [16]. The only exceptions are represented by the ligands of NKG2D, as mentioned above, by CD48, which binds 2B4, and by NTB-A, which has been demonstrated to mediate homotypic interactions [17,18]. The ligands recognized by DNAM-1 have recently been identified [19] as the poliovirus receptor (PVR; also called CD155) and Nectin-2 (CD112), two members of the nectin family, which are also involved in cell–cell adhesion and in leukocyte extravasation [20]. Remarkably, both PVR and Nectin-2 can be overexpressed on tumour cells of different histotypes [19]. The recognition of selfligands that are expressed or overexpressed upon tumour transformation or viral-infection might be a general strategy to focus NK cells on target cells that should be promptly destroyed.
NK cells have receptors for pathogenassociated molecular patterns An alternative mode of NK-cell activation has recently been identified thanks to the discovery that human NK cells can express Toll-like receptors (TLRs) [21,22,23]. TLRs are pattern recognition receptors (PRRs), which trigger innate immune responses, providing both immediate protection against various pathogens and instructing the adaptive immune system through the induction of DC recruitment and maturation [24]. Ten different TLRs have been described in humans, and most of their specific ligands have been identified. The targets of PRRs are the pathogen-associated molecular patterns (PAMPs). These include lipopolysaccharide (LPS) of gram bacteria, which is recognized by TLR4; bacterial lipoproteins and lipoteichoic acids, which are recognized by TLR2; flagellin (recognised by TLR5); unmethylated CpG typical of bacterial and viral DNA (recognised by TLR9); and double-stranded RNA (dsRNA; recognised by TLR3) as well as single-stranded RNA (recognised by TLR7). As recently shown by Sivori et al. [21], human NK cells, independent of their status of activation, express functional TLR3 and TLR9 (although they do not seem to express other TLRs), thus enabling their response to both viral and bacterial products. In particular, dsRNA or CpG www.sciencedirect.com
can induce NK-cell priming, which, in the presence of IL-12 secreted by myeloid DCs, results in the release of abundant IFN-g and TNF-a. Moreover, under these conditions, NK cells upregulate their cytolytic activity against tumour cells and acquire the ability to kill immature myeloid DCs (iDCs) [21]. Thus, the simultaneous engagement of TLR3 expressed by both NK cells and myeloid DC might be sufficient to initiate the series of events characterizing the early phases of innate immune responses. Little is known so far regarding the possible cross-talk between human NK cells and plasmacytoid DCs (PDCs). However, as both NK cells and DCs express TLR9, it is conceivable that CpG can prime both cell types. The abundant release of type I IFN [25], a potent inducer of NK cell cytotoxicity, by PDCs suggests that NK–PDC interactions can result in enhanced anti-viral innate protection. After their recruitment to inflamed tissues, NK cells and myeloid iDCs start their dialogue by getting into close physical contact [26–28]. The formation of stimulatory synapses between the two cell types promotes the polarized secretion of IL-12, which is present in preassembled stores in DCs, towards NK cells [29]. This close cell–cell interaction appears to be required for promoting a series of events, including DC-induced NK-cell proliferation, NK-cell-mediated killing of iDCs, NK-cellmediated cytokine release and NK-cell-dependent DC maturation [4,5].
NK cell–dendritic cell interactions at inflammatory sites: impact on downstream T-cell polarisation Pathogen-induced inflammatory responses in peripheral tissues are characterized by the release of various cytokines and chemokines by resident DCs and by other cell types including endothelial cells, macrophages, neutrophils, fibroblasts, mast cells and eosinophils. Some of these factors favour the extravasation of NK cells and their subsequent priming. Indeed, the majority of circulating NK cells, characterized by the CD56+CD16+ surface phenotype, express chemokine receptors, such as CXCR1 and CX3CR1, which bind CXCL8, CCL3 and CX3CL1 [4]. Moreover, myeloid DCs that are undergoing maturation upon antigen uptake release cytokines including IL-12 and IL-15, which deeply affect the functional behaviour of primed NK cells. Indeed, IL-12 is crucial for the induction of IFN-g release by NK cells as well as for the enhancement of NK-cell cytotoxicity [3,30], whereas a membrane-bound form of IL-15 appears to play a role in the induction of NK-cell proliferation [31]. Certain types of myeloid DCs, such as Langerhans cells (LCs), do not secrete bioactive IL-12p70 but they do produce high levels of IL-15 and IL-18. LCs, however, do not induce NK-cell activation, as they lack the IL-15Ra, which is Current Opinion in Immunology 2005, 17:306–311
308 Lymphocyte effector functions
required for surface anchoring of IL-15 and presentation to NK cells [32]. During the early phases of inflammatory responses, however, the engagement of TLRs might also result in the activation of other cell types involved in innate immune responses. These include resident mast cells [33] or eosinophils [34,35], which, through the release of cytokines other than IL-12 (e.g. IL-4), can deviate the subsequent adaptive response towards a state of tolerization or towards the generation of either Th2 or unpolarized T cells [36,37]. Along this line, although short-term NK-cell exposure to IL-12 promotes the release of high levels of both IFN-g and TNF-a as well as the acquisition of cytolytic activity, exposure to IL-4 results in little cytokine production and lack of cytolytic activity. Moreover, only IL-12-exposed NK cells can promote efficient DC maturation [36]. These data suggest that IL-12-primed NK cells can contribute to the selection of mature myeloid DCs (mDCs) that are capable of optimally priming Th1 responses. On the contrary, however, NK-cell priming with IL-4 might result in abnormal DC maturation characterized by both qualitative and quantitative alterations, which could eventually result in either Th2 or tolerogenic responses [36,37].
number of iDCs available for generating suitable numbers of mDCs. Accordingly, as recently suggested, the lack of NK-cell-mediated DC killing could result in altered numbers of DCs reaching complete maturation [4,40]. Thus, depending on the type of cytokines (type I or type II) released during the early stages of an inflammatory response, by either resident or recruited cells, NK cells differentially contribute to the quality and magnitude of innate immune responses. This, in turn, is likely to impact on the subsequent adaptive immune responses, as recently suggested by several studies [36,37,41–43].
NK cells in lymph nodes
A remarkable event that can occur during NK–DC interactions is the NK-cell-mediated killing of autologous myeloid iDCs. This event is dependent on a process of NK-cell activation involving NKp30 and its still undefined ligand expressed on DCs [27]. NK-mediated DC killing is inhibited by TGF-b, as this cytokine profoundly downregulates surface expression of NKp30 [38]; however, only a fraction of peripheral blood NK cells are capable of killing autologous iDCs. This NK-cell subset does not express inhibitory KIRs specific for self-HLA class I alleles but does express the CD94–NKG2A inhibitory HLA-E-specific receptor [39]. The explanation of why only this particular subset mediates myeloid iDC killing is that these cells display a sharp downregulation of surface HLA class I molecules, which primarily affects HLA-E.
Within normal non-inflamed lymph nodes NK cells are localized in the para-follicular area next to the paracortical T-cell area [44,45]. These NK cells are homogeneously characterized by the CD56bright, CD94– NKG2A+ surface phenotype, by low levels of cytolytic activity and by the production of large amounts of IFN-g. These cells are similar to the small CD56bright CD16– NK-cell subset present in peripheral blood which accounts for approximately 10% of the total circulating NK-cell pool [30]. This peripheral blood NK-cell subset is capable of substantial proliferation in the presence of LPS-activated myeloid iDCs [46] and constitutively expresses the CCR7+ CD62Lhigh surface phenotype required for migration to secondary lymphoid compartments (SLCs). In this context, however, recent studies in mice indicated that NK cells can also be recruited in a CCR7-independent, CXCR3-dependent manner into antigen-stimulated lymph nodes. At this site, they provide an early source of IFN-g necessary for Th1 polarization [42]. Interestingly, and in contrast to the human peripheral blood CD56bright CD16– NK cell subset, which expresses very high levels of NCR (particularly NKp46) [46], the corresponding NK cells derived from SLC have virtually undetectable NKp46 and NKp30 [44,45]. This suggests that receptors undergo internalization following interaction with ligands expressed within the SLC. Remarkably, the surface expression of both NKp46 and NKp30 in SLC-derived NK cells can be upregulated by IL-2 [45].
Remarkably, NK cells can also influence the progression of DC maturation via the release of TNF-a, IFN-g and GM-CSF [26]. Moreover, additional factors, including necrotic material and heat-shock proteins generated during the NK-mediated killing of tumours, virus-infected cells or iDCs themselves, might play a role in inducing DC maturation [4,5]. It is of note that danger signals that promote the release of IL-12 by myeloid DCs also induce NK cells to initiate their editing program towards DCs. This is based on the capability of NK cells to kill myeloid DCs that underexpress HLA-class I molecules, a phenomenon that might keep in check the quality of DCs undergoing maturation and control the amplitude of DC responses. By this method, NK cells could limit the
In the SLC, a possible source of IL-2 is the antigenstimulated T cells (primed by their interaction with mDCs). In line with this concept, the combined action of IL-2 (T-cell derived) and IL-12 (DC derived) is sufficient to enable SLC NK cells to produce IFN-g [44]. Thus, one might speculate that primed T cells, soon after being primed by mDCs, release IL-2 which, in turn, would induce upregulation of NCRs in SLC NK cells (which constitutively express high-affinity IL-2 receptors). As a result, they become susceptible to activation (possibly by ligands expressed on primed [activated] T cells [11]) and start to release IFN-g. At this stage, the process could go on, even in the absence of IL-12. Indeed, this cytokine is released only for a short period of time
NK-cell-mediated selection of mature myeloid dendritic cells
Current Opinion in Immunology 2005, 17:306–311
www.sciencedirect.com
The dialogue between human NK cells and DCs Moretta 309
after the generation of mDCs (DC exhaustion) [47]. Additional cytokines, particularly IL-15, might also play a role in regulating NK-cell function within SLC. For example, mature myeloid DCs (CD83+) produce IL-15 in response to either phagocytic signals or type I IFN [48,49], whereas a membrane-bound form of IL-15 expressed by myeloid DCs can induce proliferation and survival of NK cells both in the periphery and in SLC [31].
Scientifica e Tecnologica (MIUR) and the European Union FP6, LSHB-CT-2004-503319-AlloStem. Also the financial support of Fondazione Compagnia di San Paolo, Torino, Italy, is gratefully acknowledged. I am also grateful to L Moretta for helpful discussion and for critical reading of this manuscript.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1.
Moretta A, Bottino C, Mingari MC, Biassoni R, Moretta L: What is a natural killer cell? Nat Immunol 2002, 3:6-8.
2.
Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002, 20:197-216.
3.
Biron CA: Activation and function of natural killer cell responses during viral infections. Curr Opin Immunol 1997, 9:24-34.
4.
Moretta A: Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2002, 2:957-965.
5.
Zitvogel L: Dendritic and Natural Killer Cells Cooperate in the Control/Switch of Innate Immunity. J Exp Med 2002, 195:F9-F14.
6.
Ferlazzo G, Munz C: NK cell compartements and their activation by dendritic cells. J Immunol 2004, 172:1333-1339.
7.
Moretta A, Bottino C, Vitale M, Pende D, Biassoni R, Mingari MC, Moretta L: Receptors for HLA-class I molecules in human Natural Killer cells. Annu Rev Immunol 1996, 14:619-648.
8.
Long EO: Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 1999, 17:875-904.
9.
Lopez-Botet M, Llano M, Navarro F, Bellon T: NK cell recognition of non-classical HLA class I molecules. Semin Immunol 2000, 12:109-119.
Concluding remarks Cellular interactions that occur between cells of the innate immune response have acquired increasing interest, not only with regard to the regulatory/potentiating mechanisms within innate immune responses but also because they can influence subsequent adaptive immune responses. The recent discovery that NK cells can respond to pathogen-derived products through TLRs opened a new avenue in our understanding of the general role of these cells in defence against infections. Infectious agents are known to exert the greatest selective pressure on our defensive mechanisms. Accordingly, it is not surprising that NK cells, thought to play a major role in the control of viral infections, can be also be alerted by bacterial and fungal products. Another concept that starts to emerge is that early signals delivered by cells of the innate immune system as a consequence of pathogen encounter, can shape the subsequent adaptive immunity by eliciting Th1 or Th2 responses. Thus, the type of response could reside well upstream of the DC–T helper cell interaction, and could involve cells of the innate immune system, including NK cells. A better understanding of these phenomena will help to design novel immunization protocols aimed at obtaining the most appropriate adaptive immune response. This goal could be achieved by delivering appropriate stimuli to cells of the innate immune system. One of the possible targets of such adoptive immunointervention might be the use of experimental procedures acting on the editing process by which NK cells are selecting the appropriate number and quality of DCs undergoing maturation. For example, potentiation of NK cell-mediated cytotoxicity against DCs may be capable of providing a powerful feedback mechanism to limit the excess of antigen presentation in SLCs and consequent overinflammation. In addition, the clearance of iDCs might prevent the generation of IL-10-producing regulatory T cells that may suppress both the priming and the effector phase of T cells responding against a given pathogen.
Acknowledgements This work was supported by grants awarded by Associazione Italiana per la Ricerca sul Cancro (AIRC), Istituto Superiore di Sanita` (ISS) and Ministero della Sanita`, Ministero dell’Universita` e della Ricerca www.sciencedirect.com
10. Vilches C, Parham P: KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 2002, 20:217-251. 11. Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, Biassoni R, Moretta L: Activating receptors and co-receptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 2001, 19:197-223. 12. Cerwenka A, Lanier LL: Ligands for natural killer cell receptors: redundancy or specificity. Immunol Rev 2001, 181:158-169. 13. Raulet DH: Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 2003, 3:781-790. 14. Marcenaro E, Augugliaro R, Falco M, Castriconi R, Parolini S, Sivori S, Romeo E, Millo R, Moretta L, Bottino C, Moretta A: CD59 is physically and functionally associated with natural cytotoxicity receptors and activates human NK cell-mediated cytotoxicity. Eur J Immunol 2003, 33:3367-3376. 15. Shibuya A, Campbell D, Hannum C, Yssel H, Franz-Bacon K, McClanahan T, Kitamura T, Nicholl J, Sutherland GR, Lanier LL, Phillips JH: DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 1996, 4:573-581. 16. Bottino C, Castriconi R, Moretta L, Moretta A: Cellular ligands for activating NK receptors. Trends Immunol 2005, in press. A timely overview on what is presently known on activating NK receptor– ligand interactions. 17. Falco M, Marcenaro E, Romeo E, Bellora F, Marras D, Vely F, Ferracci G, Moretta L, Moretta A, Bottino C: Homophilic interaction of NTBA, a member of the CD2 molecular family: induction of cytotoxicity and cytokine release in human NK cells. Eur J Immunol 2004, 34:1663-1672. 18. Flaig RM, Stark S, Waltzl C: Cutting edge: NTB-A activates NK cells via homophilic interaction. J Immunol 2004, 172:6524-6527. 19. Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B, Cantoni C, Grassi J, Marcenaro S, Reymond N Current Opinion in Immunology 2005, 17:306–311
310 Lymphocyte effector functions
et al.: Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 2003, 198:557-567. This study demonstrates that DNAM-1 can function as an activating NK receptor and identifies its ligands as the two nectins PVR and Nectin-2. Human NK cells, via DNAM-1, recognize and become activated by nectins expressed on tumour cells of different histotypes. 20. Reymond N, Imbert AM, Devilard E, Fabre S, Chabannon C, Xerri L, Farnarier C, Cantoni C, Bottino C, Moretta A, Dubreuil P, Lopez M: DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J Exp Med 2004, 199:1331-1341. This study is a logical follow-up of the previous one [19]. It identifies the interaction between DNAM-1 and PVR as a crucial event in monocyte migration through endothelial junctions. 21. Sivori S, Falco M, Della Chiesa M, Carlomagno S, Vitale M, Moretta L, Moretta A: CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumours and dendritic cells. Proc Natl Acad Sci USA 2004, 101:10116-10121. This paper demonstrates that human NK cells express Toll-like receptors 3 and 9 when exposed to DC-derived IL-12. Upon interaction with their ligands they activate NK cells by inducing both cytolytic activity and cytokine production. 22. Schmidt KS, Leung B, Kwong M, Zarember KA, Satyal S, Navas TA, Wang F, Godowski PJ: APC-independent activation of NK cells by the Toll-like receptor 3 agonist double-stranded RNA. J Immunol 2004, 172:138-143. This study, in line with the previous one [21], shows a TLR3-dependent, direct NK-cell activation. 23. Pisegna S, Pirozzi G, Piccoli M, Frati L, Santoni A, Palmieri G: p38 MAPK activation controls the TLR3-mediated upregulation of cytotoxicity and cytokine production in human NK cells. Blood 2004, 104:4157-4164. This paper, similar to the previous one [22], describes the TLR3-dependent NK-cell activation. The role of p38 MAPK in the activation process is also demonstrated. 24. Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 2004, 4:499-511.
33. Supajatura V, Ushio H, Nakao A, Akira S, Okumura K, Ra C, Ogawa H: Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity. J Clin Invest 2002, 109:1351-1359. 34. Nagase H, Okugawa S, Ota Y, Yamaguchi M, Tomizawa H, Matsushima K, Ohta K, Yamamoto K, Hirai K: Expression and function of Toll-like receptors in eosinophils: activation by Toll-like receptor 7 ligand. J Immunol 2003, 171:3977-3982. 35. Bjerke T, Gaustadnes M, Nielsen S, Nielsen LP, Schiotz PO, Rudiger N, Reimert CM, Dahl R, Christensen I, Poulsen LK: Human blood eosinophils produce and secrete interleukin 4. Respir Med 1996, 90:271-277. 36. Marcenaro E, Della Chiesa M, Bellora F, Parolini S, Millo R, Moretta L, Moretta A: IL12 or IL4 prime human Natural Killer cells to mediate functionally divergent interactions with dendritic cells or tumours. J Immunol 2005, 174:3992-3998. This study shows that the exposure of NK cells to distinct cytokine milieu during the early stages of inflammation has an important impact on the subsequent ability of NK cells to promote the editing program of myeloid DCs towards the generation of Th1 responses. 37. Della Chiesa M, Sivori S, Castriconi R, Marcenaro E, Moretta A: Pathogen induced-private conversations between natural killer and dendritic cells. Trends Microbiol 2005, 13:128-136. A review tracing the interactions between NK and DC in the context of pathogen infections. 38. Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A: TGFb1 inhibits expression of the NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci USA 2003, 100:4120-4125. 39. Della Chiesa M, Vitale M, Carlomagno S, Ferlazzo G, Moretta L, Moretta A: The Natural Killer Cell mediated killing of autologous dendritic cells is confined to a cell subset expressing CD94/NKG2A, but lacking inhibitory killer IG-like receptors. Eur J Immunol 2003, 33:1657-1666. This study identifies NKG2A+ KIR– cells as the human NK cell subset that displays cytolytic activity against immature DCs. The article also shows that killing is due to downregulation of surface HLA-E on DCs.
25. Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A, Colonna M: Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 1999, 5:919-923.
40. Cooper MA, Fehniger TA, Fuchs A, Colonna M, Caligiuri MA: NK cell and DC interactions. Trends Immunol 2004, 25:47-52. A timely review on the interactions between NK cells and DCs.
26. Piccioli D, Sbrana S, Melandri E, Valiante NM: Contactdependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 2002, 195:335-341.
41. Mailliard RB, Son YI, Redlinger R, Coates PT, Giermasz A, Morel PA, Storkus WJ, Kalinski P: Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function. J Immunol 2003, 171:2366-2373.
27. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C: Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 2002, 195:343-351. 28. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G: Reciprocal activating interaction between NK cells and dendritic cells. J Exp Med 2002, 195:327-333. 29. Borg C, Jalil A, Laderach D, Maruyama K, Wakasugi H, Charrier S, Ryffel B, Cambi A, Figdor C, Vainchenker W et al.: NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs. Blood 2004, 104:3267-3275. 30. Cooper MA, Fehniger TA, Caligiuri MA: The biology of human natural killer-cell subsets. Trends Immunol 2001, 22:633-640. 31. Ferlazzo G, Pack M, Thomas D, Paludan C, Schmid D, Strowig T, Bougras G, Muller WA, Moretta L, Munz C: Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc Natl Acad Sci USA 2004, 101:16606-16611. This study demonstrates a role for IL-15 bound to the surface of myeloid DCs that are in the process of inducting both NK-cell proliferation and survival. 32. Munz C, Dao T, Ferlazzo G, de Cos MA, Goodman K, Young JW: Mature myeloid dendritic cell subsets have distinct roles for activation and viability of circulating human natural killer cells. Blood 2005, 105:266-273. Current Opinion in Immunology 2005, 17:306–311
42. Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, Sallusto F: Induced recruitment of NK cells to lymph nodes provides IFN-g for Th1 priming. Nat Immunol 2004, 5:1260-1265. This outstanding study shows that NK cells can be recruited to lymph nodes by CCR7-independent mechanisms and that, by releasing IFNg, they play a crucial role in the early phases of T-cell priming. 43. Byrne P, McGuirk P, Todryk S, Mills KHG: Depletion of NK cells results in disseminating lethal infection with Bordetella pertussis associated with a reduction of antigen-specific Th1 and enhancement of Th2, but not Tr1. Eur J Immunol 2004, 34:2579. 44. Fehniger TA, Cooper MA, Nuovo GJ, Cella M, Facchetti F, Colonna M, Caligiuri MA: CD56bright natural killer cells are present in human lymph nodes and are activated by T cellderived IL-2: a potential new link between adaptive and innate immunity. Blood 2003, 101:3052-3057. This paper analyzes the distribution, phenotype and function of human NK cells that populate secondary lymphoid tissues. 45. Ferlazzo G, Thomas D, Lin SL, Goodman K, Morandi B, Muller WA, Moretta A, Munz C: The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell ig-like receptors and become cytolytic. J Immunol 2004, 172:1455-1462. This paper, similar to [44], analyzes NK cells in secondary lymphoid organs. It also provides evidence that these cells might de novo acquire KIRs at their surface. www.sciencedirect.com
The dialogue between human NK cells and DCs Moretta 311
46. Vitale M, Della Chiesa M, Carlomagno S, Romagnani C, Thiel A, Moretta L, Moretta A: The small subset of CD56brightCD16natural killer cells is selectively responsible for both cell proliferation andinterferon-gammaproduction uponinteraction with dendritic cells. Eur J Immunol 2004, 34:1715-1722. This study shows that both NK cell proliferation and production of IFN-g upon interaction with DCs are confined to the small NK subset expressing high surface densities of CD56 and lacking CD16. 47. Langenkamp A, Messi M, Lanzavecchia A, Sallusto F: Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat Immunol 2000, 1:311-316.
www.sciencedirect.com
48. Jonuleit H, Wiedemann K, Muller G, Degwert J, Hoppe U, Knop J, Enk AH: Induction of IL-15 messenger RNA and protein in human blood-derived dendritic cells: a role for IL-15 in attraction of T cells. J Immunol 1997, 158:2610-2615. 49. Jinushi M, Takehara T, Tatsumi T, Kanto T, Groh V, Spies T, Suzuki T, Miyagi T, Hayashi N: Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection. J Immunol 2003, 171:5423-5429.
Current Opinion in Immunology 2005, 17:306–311