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Originally published online as doi:10.1189/jlb.1104675 on December 16, 2004

Published online before print December 16, 2004
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(Journal of Leukocyte Biology. 2005;77:408-413.)
© 2005 by Society for Leukocyte Biology

Dendritic cells and natural killer cells interact via multiple TNF family molecules

Valeria Makarenkova*,{dagger}, Ayan K. Chakrabarti{dagger}, Jennifer A. Liberatore{dagger}, Petar Popovic*,{dagger}, Ganwei Lu{dagger}, Simon Watkins{ddagger} and Nikola L. Vujanovic*,{dagger},1

* Departments of Pathology and
{ddagger} Cell Biology and Physiology, University of Pittsburgh School of Medicine, and
{dagger} University of Pittsburgh Cancer Institute, Pennsylvania

1 Correspondence: University of Pittsburgh Cancer Institute, Hillman Cancer Center, G.17d, 5117 Centre Avenue, Pittsburgh, PA 15213-1863. E-mail: vujanovicnl{at}msx.upmc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Dendritic cells (DC) and natural killer (NK) cells are essential components of the innate immune system, which rapidly sense and eliminate invading pathogens and transformed cells, mediate inflammation, and initiate adaptive immune responses. During the early immune events, DC and NK cells interact and regulate each other. The cellular "cross talk" and its molecular mediators are believed to be critical to the quality and magnitude of innate and adaptive immune responses. The goal of the present manuscript is to identify and initially assess major molecular mediators of DC-NK cell interaction. We have previously shown that DC and NK cells constitutively express several tumor necrosis factor family ligands (TNFfLs) and corresponding TNF family receptors (TNFfRs). Therefore, DC and NK cells might be able to interact via cognate interplays of TNFfLs and TNFfRs. Here, we provide initial experimental evidence supporting this possibility. We found that combined but not individual ligation of several TNFfRs induced substantial increases in secretion of interleukin-12 and inteferon-{gamma} by DC and NK cells, respectively. In contrast, specific, individual disruptions of the engagements of the corresponding TNfL-TNFfR pairs greatly impaired DC and NK cell abilities to reciprocally mediate the increases in cytokine secretion. These findings indicate that multiple TNFfLs mediate DC-NK cell interaction.

Key Words: NK cells • interaction • TNF family ligands


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Dendritic cells (DC) and natural killer (NK) cells are essential mediators and regulators of the innate immunity, which contains infection and cancer by rapid recognition and elimination of microbial pathogens and transformed cells, induction of acute inflammation, and initiation, polarization, and regulation of adaptive immune responses [1 2 3 4 5 6 ].

DC sense pathological events in tissues via Toll-like receptors and other pattern recognition receptors, which directly recognize a wide array of molecular patterns associated with pathogens and affected cells [7 ]. The cognate process induces DC maturation and secretion of proinflammatory and immunoregulatory cytokines [i.e., interleukin (IL)-1ß, tumor necrosis factor (TNF), IL-12, IL-15, and IL-18]; enables efficient DC migration to secondary lymphoid tissues and antigen processing and presentation; and leads to initiation, polarization, and regulation of effective adaptive immune responses.

In contrast, NK cells sense pathological changes in tissues via balanced cognate activities of the NK inhibitory receptors (NKIR) and NK activating receptors (NKAR), which, respectively, recognize decreased expression of major histocompatibility complex (MHC) class I molecules and increased expression of MHC class I homologues (i.e., MICA and MICB) on affected cells [8 , 9 ]. Consequently, NKIR are silenced, and NKAR are triggered; the receptor stimulation induces activation of NK cells and increases in NK cell perforin-mediated cytotoxicity and secretion of proinflammatory and immunoregulatory cytokines [i.e., IL-1ß, TNF, interferon-{gamma} (IFN-{gamma}), and granulocyte macrophage-colony stimulating factor (GM-CSF)]. The process leads to direct elimination of affected cells, induction of inflammation, and polarization and regulation of adaptive immune responses.

Recent studies have shown that DC and NK cells do not function independently but that they interact and regulate each other and mediate maturation and activation reciprocally [10 11 12 13 14 15 16 17 18 19 20 ]. Fresh NK (fNK) cells induce in immature DC (iDC) increases in expression of maturation markers and secretion of IL-12. Reciprocally, iDC induce in fNK cells proliferation, IFN-{gamma} secretion, augmentation of perforin-mediated tumoricidal activity, and in vivo control of tumor growth. Furthermore, cocultures of iDC with fNK cells in the presence of DC maturation factors, mature DC with fNK cells, or iDC with activated NK (aNK) cells induce a more rapid and more pronounced DC-NK cell reciprocal stimulation.

In addition to the reciprocal stimulation, aNK cells [in humans, CD94/NKG2A+ killer immunoglobulin (Ig)-like receptor (KIR)–] are able to kill iDC, which express low levels of the classical MHC class I molecules and/or human leukocyte antigen-E molecule [5 , 15 , 16 , 21 22 23 24 25 26 27 ]. This selective killing of DC by NK cells is induced in high effector:target ratios and could be mediated by triggering NKp30 NKAR and CD40L on NK cells and TNF-related apoptosis-inducing ligand (TRAIL) death receptors on DC [15 , 16 , 22 , 24 , 27 ]. The elimination of DC by NK cells is believed to be an important "control switch" of the immune system, which determines the quality of evolving immune responses by removing DC that are unsuited for efficient antigen presentation and initiation of effective adaptive immune responses. It is important that allogeneic NK cells, derived from KIR/MHC-mismatched bone marrow transplants, efficiently kill host DC and leukemia cells in vivo and prevent leukemia relapses and graft-versus-host and host-versus-graft reactions. These findings show that DC and NK cells can interact in vivo and that this interaction might occur in cell-to-cell contact. They also indicate that use of KIR/MHC-mismatched bone marrow transplants may be a promising strategy for treatment of leukemia [5 ].

The sites of in vivo DC-NK cell interactions have not been defined yet. However, DC and NK cells have been found in close proximity to each other in inflamed and tumor tissues as well as in draining lymph nodes. Therefore, they might interact in these tissues in vivo [28 ]. The interaction might induce enhancement of innate immunity, T helper cell type 1 (Th1) polarization, and amplification of antigen-specific immune responses. These immune processes might be essential for the effective elimination of invading pathogens and transformed cells.

The exact mechanisms and mediators that govern DC-NK cell interaction are largely unknown. The available published evidences clearly suggest that DC-NK cell interaction is only fully effective in direct cell-to-cell contact and is not functional or is functional at low levels across the transwell membrane [10 , 14 15 16 ]. Therefore, DC and NK cells might preferentially interact via cell membrane-bound molecules, although secreted molecules could also participate in this process but at a low level [14 , 15 ].

DC and NK cells express a variety of biologically active cell membrane-bound and secreted ligands and corresponding receptors, which cognate engagement could reciprocally mediate important biological responses. These molecules include the chemokines CC chemokine ligand 3 and CXC chemokine ligand 8, produced by DC, and IL-8 and macrophage-inflammatory protein 1, produced by NK cells [29 30 31 ]; the cell adhesion molecules lymphocyte function-associated antigen 1 and intercellular adhesion molecule 1, expressed on both cell types [1 , 6 , 17 , 29 30 31 ]; the costimulatory molecules CD80 and CD86, expressed on DC, and their receptor CD28, expressed on NK cells [21 , 32 ]; the NKAR NKG2D, expressed on NK cells, and its inducible ligands, expressed on DC [18 , 33 ]; and the cytokines IL-12, IL-15, and IL-18, secreted by DC, and IFN-{gamma} and GM-CSF, secreted by NK cells [1 , 6 ]. We have shown that DC and NK cells also express the TNF family ligands (TNFfLs) TNF, lymphotoxin (LT)-{alpha}1ß2, FasL, and/or CD40L as well as the corresponding TNF family receptors (TNFfRs) TNF receptor 2 (TNFR2), LT-ßR, Fas, and CD40 [34 , 35 ].

TNFfLs are pleiotropic, cell membrane-bound and secreted molecules, which mediate such diverse and important functions as apoptotosis, inflammation, and immunoregulation [36 37 38 39 ]. Some of TNFfLs expressed by DC and NK cells, in particular, TNF, CD40L, and LT-{alpha}1ß2, are potent mediators of DC maturation and NK cell activation [36 37 38 39 ]. These important biological responses are also induced in DC-NK cell interaction. In addition, it has been recently shown in humans that anti-TNF neutralizing antibodies can decrease the NK cell-mediated stimulation of CD86 expression by DC, indicating that TNF might be a mediator of DC maturation, which occurs in the DC-NK cell interaction [14 , 15 ]. These findings indicate that TNF and some other members of TNFfLs might be important mediators of DC-NK cell interaction and reciprocal stimulation. In the present study, we provide the first experimental evidence supporting the hypothesis.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Mice
Eight-week-old female, normal and TNF-deficient (TNF–/–) C57BL/6 mice were obtained from Taconic (Germantown, NY) and The Jackson Laboratory (Bar Harbor, ME), respectively. The mice were housed at the University of Pittsburgh Cancer Institute (UPCI) Animal Facility (PA). The experimental animal studies were performed in accordance with the protocols approved by the University of Pittsburgh Institutional Animal Care and Use Committee.

Reagents and antibodies
Low toxic rabbit complement was obtained from Accurate Chemical and Scientific Corp. (Westbury, NY). Mouse and human recombinant (hr) GM-CSF and IL-4 were purchased from the R&D Systems (Minneapolis, MN). hrIL-2 was provided by the Chiron-Cetus Corp. (Emeryville, CA). Escherichia coli lipopolysaccharides (LPS) was obtained from Sigma Chemical Co. (St. Louis, MO). Soluble recombinant mouse (srm)TNF was purchased from Alexis (San Diego, CA). Hybridomas producing rat anti-mouse CD4 (clone GK1.5, TIB207), CD8 (clone 2.43, TIB217), and CD45/B220 (clone RA3-3A1/6.1, TIB146) monoclonal antibodies (mAb) were obtained from American Type Culture Collection (Manassas, VA). Magnetic cell-sorter (MACS) NK cell isolation kit, which contains the biotin-antibody cocktail (anti-CD4, -CD5, -CD8{alpha}, -CD19, -Ly-6G, -Ter-119 mAb), antibiotin microbeads, and magnetic columns, was purchased from Miltenyi Biotec (Auburn, CA). Fluorochrome-conjugated anti-mouse NK1.1, CD3, CD14, CD19, and CD11c mAb and corresponding isotype-nonreactive control mAb were obtained from BD PharMingen (San Diego, CA). Rat anti-mouse TNF mAb (Pierce-Endogen, Rockford, IL), hamster anti-mouse CD40L mAb (BD PharMingen), hamster anti-mouse FasL mAb (MBL, Watertown, MA), and isotype- and species-matched, nonreactive control mAb (BD PharMingen) were used in blocking experiments. 5-Chloromethylfluorescein diacetate (CMFDA; green fluorescent dye) and 4-chloromethyl benzoyl amino tetramethyl rhodamine (CMTMR; orange fluorescent dye) were purchased from Molecular Probes (Eugene, OR). Mouse IL-12p70 and IFN-{gamma} enzyme-linked immunosorbent assay (ELISA) kits were obtained from R&D Systems.

Generation of DC
Human iDC were generated by 7-day stimulation of purified peripheral blood monocytes with GM-CSF and IL-4, as described previously [35 ].

Mouse iDC were produced from lineage marker-negative bone marrow cells, which were obtained by flashing bone marrow cavities of femurs and tibias. Bone marrow cells were depleted of erythrocytes by hypotonic lysis and of lineage marker-positive cells by treatment with anti-CD4, -CD8, and -B220 mAb (UPCI, Hybridoma Facility) and rabbit complement (Accurate Chemical and Scientific Corp.). After depletion of the mature hematopoietic cells, bone marrow cells were resuspended (0.5x106/ml) in complete cell culture medium (CM), which was constituted of RPMI-1640 medium supplemented with 0.1 mM nonessential amino acids, 2 mM sodium pyruvate, 1 mM L-glutamine, 100 µg/ml streptomycin, 100 U/ml penicillin, 20 mM HEPES buffer, 10% heat-inactivated fetal bovine serum (all from Life Technologies, Grand Island, NY), and 50 µM 2-mercaptoethanol (Bio-Rad, Hercules, CA) and cultured for 6 days in the presence of rmGM-CSF and IL-4 (R&D Systems, 15 and 7.5 ng/ml, respectively). Thus, generated iDC were 95% CD11c+lineage markers–.

Purification and activation of NK cells
Purified human peripheral blood fNK cells were obtained as described previously [34 ].

Mouse aNK cells were generated from purified, splenic fNK cells. Splenocytes were depleted of erythrocytes by hypotonic lysis, and their NK1.1+ cells were purified by negative immunoselection using MACS NK cell isolation kit (Miltenyi Biotec), as recommended by the manufacturer. Thus, purified fNK cells were consistently ≥75% NK1.1+CD3–. Purified fNK cells were resuspended in CM (0.1x106/ml), supplemented with 6000 IU/ml IL-2, and cultured for 6 days. In this culture, aNK cells were generated, expanded ten- to 20-fold, and consistently ≥97% NK1.1+CD3–.

DC-NK cell-binding assay
DC and NK cells were labeled with 1.25 µM CMFDA and CMTMR fluorescent dyes, respectively. The labeled cells were mixed in a 1:1 ratio, pelleted by centrifugation, and incubated for 10 min at 37°C. Next, the cell pellet was gently resuspended. The resulted cell suspension was added onto chamber slides and additionally incubated for 20 min at 37°C. The cells were then fixed with 1% paraformaldehyde and analyzed using a confocal microscope.

DC-NK cell coculture and cytokine testing
Day 6 of their induction with cytokines, iDC and aNK cells were harvested, seeded individually, or mixed in a 1:1 ratio (0.5x106/ml each) in 24-well plates and additionally cultured for 48 h in the absence or presence of LPS (0.1–2 µg/ml) and/or IL-2 (6000 IU/ml). In reconstitution experiments, TNF–/– DC and NK cells were cocultured in the absence or presence of rTNF (5 ng/ml). In blocking experiments, normal mouse DC and NK cells were cocultured in the presence of isotype control, anti-TNF, anti-CD40L, or anti-FasL mAb (20 µg/ml). Following the cultures, cell culture-conditioned media were collected and assessed for the presence and quantity of IL-12p70 and IFN-{gamma} using R&D Systems ELISA kits. Data were presented as means of triplicates of IL-12p70 and IFN-{gamma} pg/0.5 x 106 cells/ml. SD were <5% of means.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Resting DC and NK cells express cell membrane-bound forms but do not significantly produce soluble forms of TNFfLs [34 , 35 ]. In contrast, activated DC and NK cells express cell membrane-bound forms and secrete soluble forms of TNFfLs [35 , 40 ]. Therefore, if resting DC and NK cells interact via TNF family molecules (TNFfMs), they should do that exclusively in cell-to-cell contact. In contrast, if activated DC and NK cells interact via TNFfMs, they should do that in cell-to-cell contact and at a distance (across the transwell membrane). We initially assessed these possibilities and examined the interactions of human or mouse iDC with autologous fNK or aNK cells. We found that 10–30 min coincubation of iDC and fNK cells in cell-to-cell contact led to their rapid binding and formation of tight conjugates via the interplays of large portions of plasma membranes (Fig. 1 ). Thirty-minute cocultures of iDC and fNK cells in cell-to-cell contact reciprocally induced activation of nuclear factor (NF)-{kappa}B p65. TNFfLs could be mediators of the NF-{kappa}B activation in interacting DC and NK cells, as triggering of TNFR2, LT-ßR, and CD40 has been shown to activate NF-{kappa}B [38 , 39 ]. Next, 5 h coincubations of iDC and fNK cells in cell-to-cell contact but not separated by the transwell membrane reciprocally induced increases in expression of TNF, TNFR2, CD40L, CD40, FasL, Fas, and TRAIL mRNAs. In addition, 24 h cocultures of iDC and fNK cells or aNK cells in cell-to-cell contact induced augmentation of NK cell perforin-mediated and DC/NK cell TNFfL-mediated, tumoricidal activities (data not shown). In contrast, 48–72 h coculture of iDC with aNK cells but not with fNK cells in direct cell-to-cell contact or separated by the transwell membrane reciprocally induced secretion of IL-12p70 and IFN-{gamma}, respectively. However, this stimulation was two- to threefold higher in the cell-to-cell contact than across the transwell membrane (data not shown). Furthermore, fNK cells and aNK cells were able to help iDC to prime naïve T cells and induce cytotoxic T lymphocytes to melanoma-associated peptides p53, gp100, and melanoma antigen recognized by T cells, and this immune function was also effectively mediated in direct cell-to-cell contact and was notably greater with aNK cells than fNK cells (data not shown). The data show that fNK cells interact with DC only in direct cell-to-cell contact, and aNK cells can do so mostly in cell-to-cell contact but also at low levels across the transwell membrane. Therefore, our studies show that DC communicate with fNK cells or aNK cells exclusively or mainly via cell membrane-bound molecules. This further indicates that the mediators of DC-NK cell interaction could be cell membrane-bound TNFfLs.



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  		Figure 1. iDC and fNK cells rapidly bind each other via active involvement of their plasma membranes. Human peripheral blood monocyte-derived iDC (green) and autologous fNK cells (orange) were labeled with CMFDA and CMTMR fluorescent dyes, respectively. The labeled cells were mixed in 1:1 ratio and coincubated as described in Materials and Methods. The cells were then analyzed, and images were acquired using a confocal microscope. The combined fluorescent and interference images are presented.

 
To test this possibility directly, we applied agonistic gene knockout and antagonistic approaches. Using the agonistic approach, we found that combined but not individual triggering of the TNFfRs TNFR2, CD40, LT-ßR, and Fas with the corresponding recombinant ligands induced secretion of IL-12p70 by iDC and IFN-{gamma} by NK cells, the two major Th1 cytokines, which are reciprocally induced in DC-NK cell interaction (data not shown). Using the gene knockout approach, we examined whether disruption of the interaction between TNF and TNFR2 could subsequently reduce DC-NK cell reciprocal stimulation. We compared the biological responses in cocultures of normal mouse and TNF–/– mouse iDC and aNK cells. We found that TNF–/– iDC and aNK cells were three- to tenfold less potent than normal iDC and aNK cells to stimulate IL-12p70 secretion by DC reciprocally (Table 1 ) and killing of YAC-1 tumor cell targets (data not shown) and secretion of IFN-{gamma} by NK cells (Table 2 ). Addition of srTNF to the coculture of iDC and aNK cells (Table 2) but not during in vitro generation of iDC (data not shown) fully restored the ability of TNF–/– DC to stimulate TNF–/– NK cells to produce IFN-{gamma}. Therefore, the impairment of TNF–/– DC and NK cells to collaborate was caused directly by the absence of TNF but not indirectly by potential maturation defects of DC, which could occur in the absence of TNF. Finally, using the antagonistic approach by applying specific blocking receptor-Fc constructs or antibodies, we examined the effects of individual or combined disruption of TNF-TNFR2, LT-{alpha}1ß2-LT-ßR, CD40L-CD40, and FasL-Fas ligand receptor pairs on DC-NK cell reciprocal activation. We found that the disruption of engagements of the each individual TNFfL-TNFfR pair notably inhibited DC-NK cell interaction and consequent reciprocal induction of expression of TRAIL and CD40L mRNAs (data not shown) as well as secretion of IL-12p70 and IFN-{gamma} (Table 3 , data not shown for LT-{alpha}1ß2-LT-ßR).


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  		Table 1. TNF–/– NK Cells Are Impaired in the Ability to Enhance IL-12p70 Secretion by DCa

 

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  		Table 2. TNF–/– DC Are Impaired in the Ability to Enhance IFN-{gamma} Secretion by NK Cellsa

 

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  		Table 3. Disruption of the TNF, CD40L, and FasL Engagements with Their Cognate Receptors Using the Ligand-Neutralizing Antibodies Impairs the Abilities of DC and NK Cells to Stimulate IFN-{gamma} and IL-12p70 Secretion Reciprocally, Respectivelya

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study shows that DC and NK cells interact and stimulate each other reciprocally via cognate interplays of their transmembrane TNF-TNFR2, CD40L-CD40, LT-{alpha}1ß2-LT-ßR, and FasL-Fas ligand receptor pairs. It also indicates that the multiple TNFfL-TNFfR pairs mediate DC-NK cell interaction by simultaneous engagements in which all the involved ligand receptor pairs have a similar, important role. A possible explanation for these findings is as follows: TNFR2, LT-ßR, and CD40 possess specific cytoplasmic domains of homology [PXQX(T/S)], and upon their ligation, the receptors recruit and interact with adaptor molecules, TNFR-associated factors (TRAFs). TNFR2 interacts with TRAF1 and TRAF2, LT-ßR interacts with TRAF3 and TRAF5, and CD40 interacts with TRAF2, TRAF3, TRAF5, and TRAF6 [41 ] (Fig. 2 ). In addition, triggering of TNFR1 or Fas recruits the apoptosis signaling molecules and TRAF1 and TRAF2. Furthermore, reverse signaling via TNFfLs (e.g., FasL and CD40L) induces inflammatory responses and might also stimulate TRAF signaling pathway [22 , 41 ]. It is important that four TRAFs are shared by the TNFfRs, and it appears that their recruitments initiate the common TRAF signaling pathway, which leads to the induction of NIK, IKK, and I{kappa}B phosphorylation and consequently, activation and translocation into the nucleus of NF-{kappa}B, expression of cytokine genes, production of cytokines, and inflammation (Fig. 2) . Therefore, the simultaneous engagements of multiple TRAF-recruiting TNFfL-TNFfR pairs expressed on DC and NK cells may induce reciprocally simultaneous multifocal recruitments of multiple TRAFs and simultaneously mediate multiple, similar signaling events, which converge into a streamline of a strong signal (Fig. 2) . A reason for the necessity of the simultaneous engagements of each of the multiple heterologous TNFfL-TNFfR pairs to induce significant biological responses of interacting DC and NK cells might be a low cell-surface expression of TNFfLs and TNFfRs on these cells [34 , 35 , 40 ], which individual expression levels and large molecular distances unable their homologous but enable their heterologous polymerization and cross-linking. The simultaneous, heterologous engagements and cross-linking of multiple TNFfMs induce an appropriate and strong signal, which mediates significant biological responses. The hypothesis is under our current investigation.



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  		Figure 2. Model of DC-NK cell interaction and signaling via multiple transmembrane TNFfLs and TNFfRs. The model indicates that DC and NK cells express multiple, complementary TNFfLs and TNFfRs at low levels and therefore, interact and mediate reciprocal stimulation via simultaneous, cognate engagements of the TNFfMs and consequent multifocal recruitments of multiple TRAFs and activation of TRAF signaling pathways. This heterologous ligand receptor interaction induces in interacting DC and NK cells NF-inducing kinase (NIK), inhibitor of {kappa}B (I{kappa}B) kinase (IKK), and I{kappa}B phosphorylation (P), NF-{kappa}B activation and translocation into the nucleus, and expression of cytokines, which may result in the inflammatory response.

 


   ACKNOWLEDGEMENTS
 
This work was supported by National Institute of Dental and Craniofacial Research Grants 1-P60 DE13059 and RO1 DE14775.

Received November 19, 2004; accepted November 24, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Trinchieri, G. (1989) Biology of natural killer cells Adv. Immunol. 47,187-376[Medline]
  2. Robertson, M. J., Ritz, J. (1990) Biology and clinical relevance of human NK cells Blood 76,2421-2438[Free Full Text]
  3. Lanier, L. L., Phillips, J. H. (1992) Natural killer cells Curr. Opin. Immunol. 4,38-42[CrossRef][Medline]
  4. Moretta, A. (2002) Natural killer cells and dendritic cells:randezvous in abused tissues Nat. Rev. Immunol. 2,957-964[CrossRef][Medline]
  5. Ruggeri, L., Capanni, M., Urbani, E., Perruccio, K., Shlomchik, W. D., Tosti, A., Posati, S., Rogaia, D., Frassoni, F., Aversa, F., Martelli, M. F., Velardi, A. (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopietic transplants Science 295,2097-2100[Abstract/Free Full Text]
  6. Banchereau, J., Steinman, R. M. (1998) Dendritic cells and the control of immunity Nature 392,245-252[CrossRef][Medline]
  7. Kapsenberg, M. L. (2003) Dendritic-cell control of pathogen-driven T-cell polarization Nat. Rev. Immunol. 3,984-993[CrossRef][Medline]
  8. Moretta, L., Bottino, C., Ferlazzo, G., Pende, D., Melioli, G., Mingari, M. C., Moretta, A. (2003) Surface receptors and functional interactions of human natural killer cells: from bench to the clinic Cell. Mol. Life Sci. 60,2139-2146[CrossRef][Medline]
  9. Farag, S. S., Fehniger, T. A., Ruggeri, L., Velardi, A., Caligiuri, M. A. (2002) Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect Blood 100,1935-1947[Abstract/Free Full Text]
  10. Fernandez, N. C., Lozier, A., Flament, C., Ricciardi-Castagnoli, P., Bellet, D., Suter, M., Pericaudet, M., Tursz, T., Maraskovsky, E., Zitvogel, L. (1999) Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo Nat. Med. 5,405-411[CrossRef][Medline]
  11. Goodier, M., Londei, M. (2000) Lipopolysaccharide stimulates the proliferation of human CD56+CD3– NK cells: a regulatory role of monocytes and IL-10 J. Immunol. 165,139-147[Abstract/Free Full Text]
  12. Osada, T., Nagawa, H., Kitayama, J., Tsuno, N. H., Ishihara, S., Takamizawa, M., Shibata, Y. (2001) Peripheral blood dendritic cells, but not monocyte-derived dendritic cells, can augment human NK cell function Cell. Immunol. 213,14-23[CrossRef][Medline]
  13. Yu, Y., Hagihara, M., Ando, K., Gansuvd, B., Matsuzawa, H., Tsuchiya, T., Ueda, Y., Inoue, H., Hotta, T., Kato, S. (2001) Enhancment of human cord blood CD34+cell-derived NK cell cytotoxicity by dendritic cells J. Immunol. 166,1590-1600[Abstract/Free Full Text]
  14. Gerosa, F., Baldani-Guerra, B., Nisii, C., Marchesini, V., Carra, G., Trinchieri, G. (2002) Reciprocal activating interaction between natural killer cells and dendritic cells J. Exp. Med. 195,327-333[Abstract/Free Full Text]
  15. Piccioli, D., Sbrana, S., Melandri, E., Valiante, N. M. (2002) Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells J. Exp. Med. 195,335-341[Abstract/Free Full Text]
  16. Ferlazzo, G., Tsang, M. L., Morretta, L., Melioli, G., Steinman, R. M., Munz, C. (2002) Human dendritic cells activate resting natural killer (NK) cells and are recognized via NKp30 receptor by activated NK cells J. Exp. Med. 195,343-351[Abstract/Free Full Text]
  17. Poggi, A., Carosio, R., Spaggiari, G. M., Fortis, C., Tambussi, G., Dell’Antonio, G., Cin, E. D., Rubatelli, A., Zocchi, M. R. (2002) NK cell activation of dendritic cells is dependent on LFA-1-mediated induction of calcium-calmodulin kinase II: inhibition by HIV-1 Tar C-terminal domain J. Immunol. 168,95-101[Abstract/Free Full Text]
  18. Jinushi, M., Takehara, T., Kanto, T., Tatsumi, T., Groh, V., Spies, T., Miyagi, T., Suzuki, T., Sasaki, Y., Hayashi, N. (2003) Critical role of MHC class I-related chain A and B expression on IFN-{alpha} stimulated dendritic cells in NK cell activation: impairment in chronic hepatitis C virus infection J. Immunol. 170,1249-1256[Abstract/Free Full Text]
  19. Maillard, R. B., Son, Y-I., Redlinger, R., Coates, P. T., Giermasz, A., Morel, P. A., Storkus, W. J., Kalinski, P. (2003) Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function J. Immunol. 171,2366-2373[Abstract/Free Full Text]
  20. Andrews, M. D., Scalzo, A. A., Yokoyama, W. M., Smyth, M. J., Degli-Esposti, M. A. (2003) Functional interactions between dendritic cells and NK cells during viral infection Nat. Immunol. 4,175-181[CrossRef][Medline]
  21. Geldhof, A. B., Moser, M., Lespagnard, L., Thielemans, K., De Baetselier, P. (1998) Interleukin-12-activated natural killer cells recognize B7 costimulatory molecules on tumor cells and autologous dendritic cells Blood 91,196-206[Abstract/Free Full Text]
  22. Carbone, E., Terrazzano, G., Ruggiero, G., Zanzi, D., Ottaiano, A., Manzo, C., Karre, K., Zappacosta, S. (1999) Recognition of autologous dendritic cells by human NK cells Eur. J. Immunol. 29,4022-4029[CrossRef][Medline]
  23. Ferlazzo, G., Semino, C., Melioli, G. (2001) HLA class I molecule expression is up-regulated during maturation of dendritic cells, protecting them from natural killer cell-mediated lysis Immunol. Lett. 76,37-41[CrossRef][Medline]
  24. Spaggiari, G. M., Carosio, R., Pende, D., Marcenaro, S., Rivera, P., Zocchi, M. R., Moretta, L., Poggi, A. (2001) NK cell-mediated lysis of autologous antigen presenting cells is triggered by the engagement of the phosphatidylinositol 3-kinase upon ligation of the natural cytotoxicity receptors NKp30a and NKp46 Eur. J. Immunol. 31,1656-1665[CrossRef][Medline]
  25. Della Chiesa, M., Vitale, M., Carlomagno, S., Ferlazzo, G., Moretta, L., Moretta, A. (2003) 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. 33,1657-1666[CrossRef][Medline]
  26. Ferlazzo, G., Morandi, B., D’Agostino, A., Meazza, R., Melioli, G., Moretta, A., Moretta, L. (2003) The interaction between NK cells and dendritic cells in bacterial infections results in rapid induction of NK cell activation and in the lysis of uninfected dendritic cells Eur. J. Immunol. 33,306-313[CrossRef][Medline]
  27. Hayakawa, Y., Screpanti, V., Yagita, H., Grandien, A., Ljunggren, H-G., Smith, M. J., Chambers, B. J. (2004) NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy J. Immunol. 172,123-129[Abstract/Free Full Text]
  28. Ferlazzo, G., Munz, C. (2004) NK cell compartments and their activation by dendritic cells J. Immunol. 172,1333-1339[Free Full Text]
  29. Cooper, M. A., Fehniger, T. A., Caligiuri, M. A. (2001) The biology of human natural killer-cell subsets Trends Immunol. 22,633-640[CrossRef][Medline]
  30. Cooper, A. M., Fehniger, T. A., Fuchs, A., Colonna, M., Caligiuri, M. A. (2004) NK cell and DC interactions Trends Immunol. 25,47-52[CrossRef][Medline]
  31. Figdor, C. G. (2003) Molecular characterization of dendritic cells operating at the interface of innate or acquired immunity Pathol. Biol. (Paris) 51,61-63[Medline]
  32. Lanier, L. L. (2001) On guard-activating NK cell receptors Nat. Immunol. 2,23-27[CrossRef][Medline]
  33. Yokoyama, W. M., Plougastel, B. F. M. (2003) Immune functions encoded by the natural killer gene complex Nat. Rev. Immunol. 3,304-316[CrossRef][Medline]
  34. Kashii, Y., Giorda, R., Herberman, R. B., Whiteside, T. L., Vujanovic, N. L. (1999) Constitutive expression and role of the tumor necrosis factor family ligands in apoptotic killing by human natural killer cells J. Immunol. 163,5358-5366[Abstract/Free Full Text]
  35. Lu, G., Janjic, B. M., Janjic, J., Whiteside, T. L., Storkus, W. J., Vujanovic, N. L. (2002) Innate direct anticancer effector function of human immature dendritic cells. II. Role of TNF, LT-{alpha}1ß2, Fas ligand and TRAIL J. Immunol. 168,1831-1839[Abstract/Free Full Text]
  36. Beutler, B., van Huffel, C. (1994) Unraveling function in the TNF ligand and receptor families Science 264,667-668[Free Full Text]
  37. Smith, C. A., Farrah, T., Goodwin, R. G. (1994) The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death Cell 76,959-969[CrossRef][Medline]
  38. Gruss, H. J. (1996) Molecular, structural, and biological characteristics of the tumor necrosis factor ligand superfamily Int. J. Clin. Lab. Res. 26,143-159[Medline]
  39. Lotz, M., Setareh, M., von Kempis, J., Schwarz, H. (1996) The nerve growth factor/tumor necrosis factor receptor family J. Leukoc. Biol. 60,1-7[Abstract]
  40. Vujanovic, N. L. (2001) Role of TNF family ligands in antitumor activity of natural killer cells Int. Rev. Immunol. 20,415-437[Medline]
  41. Arch, R. H., Gedrich, R. W., Thompson, C. B. (1998) Tumor necrosis factor receptor-associated factors (TRAFs)—a family of adapter proteins that regulates life and death Genes Dev. 12,2821-2830[Free Full Text]



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