Regulation of NK Cell Activation by DC

Pioneering studies by Fernandez et al. showed that the DC growth factor Flt3-L, which promotes both DC and NK cell expansion, was also capable of promoting in nude mice a NK cell-dependent antitumor effect that could be significantly abrogated by treatment with an anti-CD8a mAb [27]. These experiments suggested a direct role for CD8a+ DC in NK cell triggering in vivo. This role was directly demonstrated by the adoptive transfer of the mouse DC cell line D1 into AK7 mesothelioma tumors, leading to tumor eradication except in nude mice in which NK cells were depleted by concomitant administration of neutralizing anti-NK1.1 Ab. Furthermore, it was demonstrated that in vitro bone marrow-derived DC (BM-DC) or D1 cells stimulated by TNFa could stimulate NK cell effector functions. Neither macrophages nor NK cell targets could promote NK cell lytic activity in vitro to the levels induced by mature DC. However, the molecular mechanisms by which TNFa-stimulated DC mediate NK cell activation remain unknown [27]. Afterwards, most of the murine studies used BM-DC stimulated with TLR4 ligands such as LPS or Escherichia coli bacteria. After TLR4 triggering, BM-DC propagated in the absence of IL-4, transiently produced IL-2 [28,29], and induced IL-2-dependent IFNy secretion by mouse NK cells in vitro [30] (Fig. 1a). In this setting, low-level type IIFN produced by BM-DC stimulated by E. coli promoted NK cell cytotoxicity [30]. In this setting, NK cell activation was dependent on cell-to-cell contact but independent of IL-12 and IL-18. In vivo, inoculation of E. coli promoted NK cell IFNy production and DC represented a source of IL-2 contributing to NK cell activation [30].

However, IL-2 was not produced by BM-DC propagated in the presence of IL-4 and stimulated with LPS [31]. Rather, IL-15 and IL-15Ra were upregulated and play a critical role to promote NK cell cytotoxicity and IFN-y secretion in vitro [32] (Fig. 1b). Borg et al. [33] by using cells from IL-12 genetically deficient mice, revealed a critical role for IL-12 in NK cell IFN-y secretion promoted by mature mouse DC. In the absence of LPS stimulation, BM-DC generated in the presence of IL-4 were able to activate NK cells, unlike BM-DC generated in the absence of IL-4. The triggering receptor expressed on myeloid cells-2 (TREM2) associated with KARAP/DAP12 adaptor molecule was upregulated on BM-DC by IL-4 and was involved in DC-mediated NK cell activation [34] (Fig. 1c).

The molecular mechanisms involved in NK cell triggering by human DC start to be unraveled. Mature DC or immature DC in the presence of maturation stimuli, such as LPS or Mycobacterium tuberculosis or IFNa, are able to activate NK cells [35-38]. The crucial role of IL-12 in IFN-y secretion by

Cell Activation

Fig. 1a-d Regulation of the DC-mediated NK cell activation in mouse models. TLR ligands, protooncogenes BCR/ABL and c-kit, and Treg can modulate the DC-NK cell dialogue. TLR4 ligands promote IL-2 and IFNa production when triggering a DC differentiated in the absence of IL-4 (a). In the presence of IL-4, TLR4 ligands promote IL-15Ra andIL-15 expression required for NK cell activation (b). In DC propagated in GM-CSF and IL-4, but not stimulated with TLR4 ligands, the TREM2/KARAPDAP12 signaling pathway is critical for the bidirectional activation (c). The BCR/ABL tyrosine kinase endows DC with NK cell stimulatory capacities in a NKG2D-dependent manner by upregulating Rae-1 expression (d). The c-kit receptor and CD4+CD25+ Treg inhibit the bidirectional DC-NK cell interaction (c)

Fig. 1a-d Regulation of the DC-mediated NK cell activation in mouse models. TLR ligands, protooncogenes BCR/ABL and c-kit, and Treg can modulate the DC-NK cell dialogue. TLR4 ligands promote IL-2 and IFNa production when triggering a DC differentiated in the absence of IL-4 (a). In the presence of IL-4, TLR4 ligands promote IL-15Ra andIL-15 expression required for NK cell activation (b). In DC propagated in GM-CSF and IL-4, but not stimulated with TLR4 ligands, the TREM2/KARAPDAP12 signaling pathway is critical for the bidirectional activation (c). The BCR/ABL tyrosine kinase endows DC with NK cell stimulatory capacities in a NKG2D-dependent manner by upregulating Rae-1 expression (d). The c-kit receptor and CD4+CD25+ Treg inhibit the bidirectional DC-NK cell interaction (c)

human NK cells stimulated by monocyte- or CD34+-derived DC and LPS or by peripheral blood mDC in response to TLR3 or TLR8 ligands has been formally demonstrated. Other cytokines, such as IL-18, and/or cellular contacts are also involved [26,33,36] (S. Burg, F. Briere, G. Trinchieri, C. Caux, P. Garrone, unpublished results). However, NK cell activation by DC also requires direct cell-to-cell contacts and depends on the adhesion molecule LFA-1 [39]. The formation of DC/NK cell conjugates was found to depend on cytoskeleton remodeling and lipid raft mobilization in DC. BM-DC derived from mice with loss of function of the Wiskott Aldrich syndrome protein, a major cytoskeletal regulator expressed in hematopoietic cells, fail to promote NK cell lytic ac tivity and IFN-y secretion [33]. Moreover, disruption of the DC cytoskeleton with pharmacological agents abolished the DC-mediated NK cell activation. Synapse formation promoted the polarized secretion of preassembled stores ofIL-12byDC toward the NK cell. Synaptic delivery ofIL-12byD C was found to be required for IFN-y secretion by NK cells, as assessed with inhibitors of cytoskeleton rearrangements and Transwell experiments. Therefore, the cross-talk between LPS-activated DC and NK cells is dictated by functional synapses [33].

Upon IFNa stimulation, MHC-class I-related chain-A and -B (MICA/B), ligands for NKG2D receptor are induced on monocyte-derived DC and are responsible for NK cell activation [40]. MICA/B expression on DC is modulated not only by type IIFN but also by DC derived IL-15 [41].

Myeloid DC stimulated by TLR3 ligands and plasmacytoid DC after exposure to viruses or TLR9 ligands promote NK cell lytic activity in a type I IFN-dependent fashion [26].

Mature monocyte-derived DC and, to a much lesser extent, CD34+-derived interstitial dermal-like DC induce human NK activation and proliferation by a mechanism requiring IL-15 and IL-12. Langerhans cells (LC), in contrast, fail to induce NK cell activation, probably because of their impaired ability to produce IL-12 and IL-15Ra. They require exogenous IL-2 or IL-12 to activate NK cells in vitro [42]. However, LC can maintain NK cell survival in vitro after a proliferation phase induced by interstitial dermal DC [42].

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