The Bidirectional Crosstalk between Human Dendritic Cells and Natural Killer Cells

Dendritic cells (DCs) are professional antigen-presenting cells, which display an extraordinary capacity to induce T-cell responses. Recent findings revealed that DCs also play a crucial role in the activation of natural killer (NK) cells representing important effectors in the innate immune defense against viruses and tumors. Here, we summarize various studies investigating the bidirectional crosstalk between human DCs and NK cells. In this context, it has been reported that DCs efficiently enhance CD69 expression, proliferation, interferon (IFN)secretion and cytotoxic activity of NK cells. Cell membrane-associated molecules as well as soluble factors such as interleukin-12, tumor necrosis factor and type I IFNs contributed to DC-mediated NK cell activation. Reciprocally, the ability of human NK cells to enhance the immunostimulatory capacity of DCs was shown. Thus, NK cells promoted the maturation of DCs and markedly augmented their capacity to produce proinflammatory cytokines and to stimulate T-cell responses. The NK cell-mediated effects on DCs were dependent on cell membrane-associated molecules such as NKp30 and soluble factors such as tumor neReceived: October 21, 2010 Accepted after revision: December 7, 2010 Published online: March 11, 2011 Journal of Innate Immunity Dr. Marc Schmitz Institute of Immunology, Medical Faculty Technical University of Dresden, Fetscherstr. 74 DE–01307 Dresden (Germany) Tel. +49 351 458 6501, E-Mail marc.schmitz @ tu-dresden.de © 2011 S. Karger AG, Basel 1662–811X/11/0033–0258$38.00/0 Accessible online at: www.karger.com/jin Interaction between Dendritic Cells and Natural Killer Cells J Innate Immun 2011;3:258–263 259 tive and therapeutic antitumor responses [2] . In addition, clinical trials enrolling tumor patients revealed promising immunologic and clinical responses of tumor-associated antigen-loaded DCs administered as a vaccine [3] . Recent findings indicated that DCs also play an important role in the activation of natural killer (NK) cells, which represent important effectors in innate immunity [4] . Human blood NK cells can be subdivided into two distinct subsets based on the cell surface density of CD56 expression [5] . CD56 dim CD16 + NK cells represent the majority (approximately 90%) of NK cells and have a high cytotoxic capacity. CD56 bright CD16 – NK cells comprise approximately 10% of NK cells and produce high levels of cytokines such as interferon (IFN) and tumor necrosis factor (TNF), which play an important role in modulating immune responses. Due to their functional properties, NK cells essentially contribute to the elimination of tumor and virus-infected cells. When investigating the potential of mouse DCs to stimulate NK cells, it has been reported that FMS-like tyrosine kinase 3 ligand-expanded or adoptively transferred DCs markedly enhance NK cell-dependent antitumor effects in mice with major histocompatibility complex class-I-negative tumors [6] . Following such findings, the bidirectional crosstalk between human DCs and NK cells has been explored. The results are summarized in this review article. Human DCs Improve Effector Functions of NK Cells In recent years, several studies investigated the potential of human DCs to influence phenotype and function of NK cells. Most of these analyses were performed with monocyte-derived DCs. To obtain immature DCs, monocytes were maintained for several days in the presence of granulocyte macrophage colony-stimulating factor and IL-4. For maturation and stimulation, immature DCs were cultivated in the presence of additional factors such as TNF, IL-1 , IFN , lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid. It has been demonstrated that monocyte-derived DCs markedly enhance the expression of the activation marker CD69 on the surface of NK cells [7–12] . Soluble factors such as type I IFNs as well as direct cell-to-cell contact were shown to be important for DC-mediated upregulation of CD69 on NK cells [7–9, 12] . Thus, major histocompatibility complex class-I-related chain (MIC) A and B representing ligands for the activating NK cell receptor NKG2D were induced on monocyte-derived DCs upon IFNstimulation and contributed to the upregulation of CD69 on NK cells [9] . More recently, it has been reported that the recognition of influenza-infected monocyte-derived DCs by the activating NK cell receptors NKG2D and NKp46 results in an increased CD69 expression on NK cells [12] . Further studies revealed that human monocyte-derived DCs are also able to efficiently promote NK cell proliferation [10, 13–17] . When distinguishing between CD56 dim CD16 + and CD56 bright CD16 – NK cell subsets, Vitale et al. [10] demonstrated that activated monocytederived DCs only increased expansion of CD56 bright CD16 – NK cells. In contrast, IL-2 induced a non-selected, homogeneous proliferation of both NK cell populations. Cell-to-cell contact essentially contributed to DC-mediated NK cell proliferation. Thus, it has been documented that the interaction between CD40 on DCs and CD40L on NK cells as well as B7 molecules on DCs and CD28 on NK cells plays an important role [13] . IL-15 expressed on the surface of activated monocyte-derived DCs also mediated enhanced NK cell proliferation [15] . In addition, IL-12 contributed to this effect [13] . Further studies explored the potential of monocytederived DCs to modulate cytokine production of NK cells. Monocyte-derived DCs induced the release of IFNby NK cells [9, 10, 12–15, 17–19] . When investigating the underlying mechanisms, it has been demonstrated that IL-12 essentially contributes to this effect [9, 10, 12, 13, 15, 18] . DC-mediated induction of IFN production by NK cells also required direct cell-to-cell contact [12] . Recently, Borg et al. [18] reported that the formation of stimulatory synapses promoted the polarized secretion of preassembled stores of IL-12 by DCs towards NK cells. In this context, the interaction of CX3CL1 expressed by DCs and CX3CR1 on NK cells induced DC-mediated IFNproduction by NK cells [19] . However, whereas IL-12 plays a major role for the induction of NK cell IFN secretion by LPS-activated DCs, other factors appear to be important for IFN-stimulated DCs mediating the same effect. Thus, it has been shown that the expression of the NKG2D ligands MICA and MICB on IFN-treated DCs is responsible for the induction of IFNproduction by NK cells [9] . In addition, Draghi et al. [12] reported that NK cell IFN secretion mediated by influenza virus-infected DCs is dependent on the ligation of the activating NK cell receptors NKp46 and NKG2D. The cytotoxic potential of NK cells plays an important role in the elimination of virus-infected and tumor cells. Therefore, the impact of human monocyte-derived DCs on the cytotoxic activity of NK cells was investigated. It has been documented that DCs efficiently improve this functional property of NK cells [8, 9, 12, 13, 16, 17, 19, 20] .