Plasmacytoid dendritic cell‐induced migration and activation of NK cells in vivo

Abstract

NK cells are cytotoxic cells of the innate immune system. They have been found to be critical in the defense against infections and also against some tumors. Recent studies have shown that NK cells require signals from accessory cells to induce their recruitment and activation at the site of infection or tumor growth. In this study, we examined whether plasmacytoid DC (pDC) could recruit and activate NK cells in vivo. When CpG-stimulated pDC were injected i.p. to C57BL/6 mice, they efficiently recruited NK cells, a process that was dependent on NK cell CXCR3 and CD62L and in part on CCR5. NK cells isolated from the peritoneum of mice inoculated with TLR7/8 or TLR9-stimulated pDC exhibited greater cytotoxicity against YAC-1 tumor cells than NK cells recovered from mice inoculated with control pDC. The present results are discussed in relation to pDC-induced NK cell migration and activation in vivo.Key words: Cellular activation . Cell migration . Costimulatory moleculers . Dendritic cells . NK cell IntroductionNK cells are lymphocytes of the innate immune system that play a crucial role in the early host defense against infections and some tumors [1]. NK cells have potent cytotoxic functions and are efficient producers of several cytokines including IFN-g, TNF-a, and GM-CSF [2]. The latter contribute to the immunoregulatory properties of NK cells, which affect anti-microbial and anti-tumor responses as well as the outcome of many autoimmune and hypersensitivity reactions [3]. By their cytotoxicity and cytokine production, NK cells can affect CTL responses in infection and tumor models as well as B-cell responses [4][5][6][7][8]. NK cells are found in both nonlymphoid and lymphoid tissues including lung, liver, blood, spleen, and LN [9]. Several studies have demonstrated that NK cells migrate to different tissues in response to stimuli, such as allergic responses, infections, or tumor growth [10][11][12][13][14][15][16][17][18][19]. Four chemokine receptors, CCR2, CCR5, CXCR3 and CX3CR1, have been shown to be particularly important for mouse NK-cell migration to various inflammatory stimulus [4,9]. However, other molecules such as CD62L, IFN-g, sphingosine 1-phosphate receptor, and TNF-a are also important for the NKcell migration in mice. For example, blocking CD62L with Ab prevents the egress of NK cells from blood into LN [4]. IFN-g modulates migration by inducing the production of CXCL10 (IP10) [20]. Thus, mice deficient in IFN-g also exhibit reduced CXCL10 production. In mice lacking sphingosine 1-phosphate receptor, NK cells accumulate in the LN and bone marrow while being absent from blood, spleen, or lungs [21]. Thus chemokine activation of NK cells is important for their recruitment to inflammatory sites. In both mice and humans, two main types of ''DC'' exist, conventional DC (cDC), including both lymphoid tissue-resident DC and migratory DC, and so-called plasmacytoid DC (pDC). In mice, cDC in the spleen can be further subdivided into the CD8a 1 and CD8a À populations. The former are involved in crosspr...

Pivotal role of plasmacytoid dendritic cells in inflammation and NK-cell responses after TLR9 triggering in mice

“…Our results are in agreement with the observation that CpG-activated pDCs injected into the mouse peritoneum were able to recruit NK cells 40 and confirm the potential role for human pDCs in NK-cell recruitment. 26,39,41 This defect in NK-cell recruitment could be explained by the fact that these cells expressed CCR2, CCR5, and CXCR3, 42 which respond to CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10.…”

Microfluidic‐based, live‐cell analysis allows assessment of NK‐cell migration in response to crosstalk with dendritic cells

“…2 and 6A), thus providing direct evidence to support an important role of DC-secreted soluble factors in the recruitment of NK cells. A number of reports demonstrated that CXCR3, other than CCR2, CCR5, and CX3CR1 receptors, was involved in the migration of cytotoxic NK cells during inflammation and their infiltration into the tumors [18,24,44,50,51]. In agreement with the published data, we found that neutralizing antibodies against CXCR3 abrogated part of the migratory response induced by the conditioned medium of the LPS-stimulated mature DCs in the trans-well system (Fig.…”

G-protein-coupled receptors in control of natural killer cell migration

“…As immature DCs express CCR1 and CCR5 [46], the receptors of CCL3-5, this suggests that NK cells attract DCs within LNs. The converse is also true, and a series of recent studies has highlighted the capacity of DCs or plasmacytoid DCs to attract NK cells via CCR5 [32] or CXCR3 [47] (Figure 2). In the spleen, DCs can also attract NK cells and other innate cells in response to inflammatory or infectious stimuli in a CXCR3-and CCL5ÀCCR5-dependent manner [48,49].…”