Dendritic Cells Mediate NK Cell Help for Th1 and CTL Responses: Two-Signal Requirement for the Induction of NK Cell Helper Function

Abstract

Early stages of viral infections are associated with local recruitment and activation of dendritic cells (DC) and NK cells. Although activated DC and NK cells are known to support each other’s functions, it is less clear whether their local interaction in infected tissues can modulate the subsequent ability of migrating DC to induce T cell responses in draining lymph nodes. In this study, we report that NK cells are capable of inducing stable type 1-polarized “effector/memory” DC (DC1) that act as carriers of NK cell-derived helper signals for the development of type 1 immune responses. NK cell-induced DC1 show a strongly elevated ability to produce IL-12p70 after subsequent CD40 ligand stimulation. NK-induced DC1 prime naive CD4+ Th cells for high levels of IFN-γ, but low IL-4 production, and demonstrate a strongly enhanced ability to induce Ag-specific CD8+ T cell responses. Resting NK cells display stringent activation requirements to perform this novel, DC-mediated, “helper” function. Although their interaction with K562 cells results in effective target cell killing, the induction of DC1 requires a second NK cell-activating signal. Such costimulatory signal can be provided by type I IFNs, common mediators of antiviral responses. Therefore, in addition to their cytolytic function, NK cells also have immunoregulatory activity, induced under more stringent conditions. The currently demonstrated helper activity of NK cells may support the development of Th1- and CTL-dominated type 1 immunity against intracellular pathogens and may have implications for cancer immunotherapy.

Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

“…On the one hand, NK-DC crosstalk is characterized by the capacity of activated NK cells to induce DC maturation with elevated IL-12p70 production and subsequently an increased capacity to induce Th1 and CTL responses [9]. This NK-induced DC maturation depends at least in part on soluble factors such as TNF-a [10] and IFN-g [11] as well as on engagement of the natural cytotoxicity triggering receptor 30 [12].…”

Optimal culture conditions for the generation of natural killer cell-induced dendritic cells for cancer immunotherapy

“…The two-signal requirement for the induction of NK ''helper'' activity was met by using freshly isolated NK cells in the presence of an additional costimulatory signal. 7,16 The presence of IFN-c (which can be induced by TLR ligands) during DC maturation overcomes maturation-associated DC 'exhaustion', yielding stable type 1-polarized DCs that produce higher levels of IL-12p70 and exhibit a dramatically enhanced capacity to induce Th1 responses. 26 It has been reported that IFN-c is produced by NK cells after 17 h of stimulation with poly(I:C), and it peaks at 48 h. 27 In our study, the level of IFN-c production in resting NK cells after 48 h of stimulation in the presence of TLR agonists and cytokines was higher than that observed in either activated NK cells or resting NK cells in the absence of costimulatory signals.…”

“…Although we did not detect any significant killing of DCs by resting NK cells or activated NK cells, it is possible that depending on the cytolytic activity of activated NK cells, the DC/NK cell ratio or the presence of particular NK cell subsets, NK cells will mainly kill or inactivate DCs, resulting in suppression of the immune response. 7 The key to the initiation of immune responses to pathogens is the recognition of pathogen associated ligands that are not normally expressed by host cells. This recognition is mediated by members of the TLR family, several of which are expressed by immature DCs 28 and NK cells.…”

“…[3][4][5][6] The presence of interferon (IFN)-c or IFN-c-producing cells, such as CD8 1 T cells or natural killer (NK) cells, at the final stages of DC maturation, leads to the development of a type 1-polarized DC subset, which produces increased levels of IL-12p70 after contact with naive Th cells and induces Th1-like differentiation in naive Th cells. 7,8 NK cells are the major lymphocyte population of the innate immune response and function through the production of cytokines and lysis of virus-infected cells or tumor cells. 9 The activation of NK cells relies on a combination of interactions with cytokine receptors, adhesion molecules and activating receptors ligated via interactions with tumors, pathogen-infected cells or other immune cells.…”

“…[12][13][14][15] Recently, NK cells have also been shown to play immunoregulatory 'helper' roles, by activating DCs and enhancing their ability to produce pro-inflammatory cytokines, as well as to stimulate Th1 and cytotoxic T lymphocyte (CTL) responses of tumor-specific CD4 1 and CD8 1 T cells, respectively. 7,16,17 In our previous study, we proposed that potent DCs were generated by NK cell-mediated maturation in the presence of Toll-like receptor (TLR) 4 agonist, and vaccination with these DCs demonstrated strong efficacy in a mouse colon cancer model. 18 Although the above data suggest that NK cells and DCs can reciprocally activate each other during the immune response, which type of NK cells (freshly isolated resting cells or previously activated cells) are most effective in inducing the activation and maturation of DCs remains unknown.…”