Mechanism of NK cell activation induced by coculture with dendritic cells derived from peripheral blood monocytes

153

115

NK cells express an array of activating and inhibitory receptors that determine NK cell responses upon triggering by cognate ligands. Although activating NK cell receptors recognize mainly ligands expressed by stressed, virus-infected, or transformed cells, most inhibitory receptors engage MHC class I, preventing NK cell activation in response to healthy cells. In this study, we provide insight into the regulation and function of additional receptors involved in mouse NK cell responses: CTLA-4 and CD28. CTLA-4 and CD28 engage the same ligands, B7-1 and B7-2, which are primarily expressed by APCs, such as dendritic cells. Our data demonstrate that activation of mouse NK cells with IL-2 induces the expression of CTLA-4 and upregulates CD28. CTLA-4 expression in IL-2–expanded NK cells was further up- or downregulated by IL-12 or TGF-β, respectively. Using gene-deficient NK cells, we show that CD28 induces, and CTLA-4 inhibits, IFN-γ release by NK cells upon engagement by the recombinant ligand, B7-1, or upon coculture with mature dendritic cells. Notably, we show that mouse NK cells infiltrating solid tumors express CD28 and CTLA-4 and respond to stimulation with recombinant B7-1, suggesting that the NK cell responses mediated by the CD28/CTLA-4:B7-1/B7-2 system could be of importance during malignant disease. Accordingly, our study might have implications for immunotherapy of cancer based on blocking anti–CTLA-4 mAbs.

Section: Discussionmentioning

confidence: 84%

CTLA-4 Is Expressed by Activated Mouse NK Cells and Inhibits NK Cell IFN-γ Production in Response to Mature Dendritic Cells

Stojanović

Fiegler

Brunner‐Weinzierl

et al. 2014

153

115

“…Yu et al (24) demonstrated the capability of CD34 ϩ cell-derived DCs to significantly improve the tumor-directed cytotoxicity and IFN-␥ secretion of NK cells. In addition, it has been shown that the expansion, IFN-␥ production, and tumoricidal potential of NK cells are increased efficiently upon interaction with monocyte-derived DCs (25)(26)(27). Cross-talk is bidirectional because activated NK cells induce immature DC activation in terms of up-regulation of MHC and costimulatory molecules, resulting in an enhancement of the allostimulatory capacity of DCs (28,29).…”

Section: Endritic Cells (Dcs)mentioning

confidence: 99%

Tumoricidal Potential of Native Blood Dendritic Cells: Direct Tumor Cell Killing and Activation of NK Cell-Mediated Cytotoxicity

Schmitz

Zhao

Deuse

et al. 2005

Dendritic cells (DCs) are characterized by their unique capacity for primary T cell activation, providing the opportunity for DC-based cancer vaccination protocols. Novel findings reveal that besides their role as potent inducers of tumor-specific T cells, human DCs display additional antitumor effects. Most of these data were obtained with monocyte-derived DCs, whereas studies investigating native blood DCs are limited. In the present study, we analyze the tumoricidal capacity of M-DC8+ DCs, which represent a major subpopulation of human blood DCs. We demonstrate that IFN-γ-stimulated M-DC8+ DCs lyse different tumor cell lines but not normal cells. In addition, we show that tumor cells markedly enhance the production of TNF-α by M-DC8+ DCs via cell-to-cell contact and that this molecule essentially contributes to the killing activity of M-DC8+ DCs. Furthermore, we illustrate the ability of M-DC8+ DCs to promote proliferation, IFN-γ production, and tumor-directed cytotoxicity of NK cells. The M-DC8+ DC-mediated enhancement of the tumoricidal potential of NK cells is mainly dependent on cell-to-cell contact. These results reveal that, in addition to their crucial role in activating tumor-specific T cells, blood DCs exhibit direct tumor cell killing and enhance the tumoricidal activity of NK cells. These findings point to the pivotal role of DCs in triggering innate and adaptive immune responses against tumors.

“…The precise events or mediators that direct DC toward immunity or tolerance are not understood. Some have postulated that CD8␣ Ϫ (myeloid) DC are inherently immunogenic while CD8␣ ϩ (lymphoid) DC are tolerogenic (2)(3)(4). However, recent studies have indicated that CD8␣ ϩ and CD8␣ Ϫ DC are not distinct populations but simply represent different maturational stages of the same DC lineage (5).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Murine Flt3 Ligand Expands Distinct Dendritic Cells with Both Tolerogenic and Immunogenic Properties

Miller

Pillarisetty

Shah

et al. 2003

Human Flt3 ligand can expand dendritic cells (DC) and enhance immunogenicity in mice. However, little is known about the effects of murine Flt3 ligand (mFlt3L) on mouse DC development and function. We constructed a vector to transiently overexpress mFlt3L in mice. After a single treatment, up to 44% of splenocytes became CD11c+ and the total number of DC increased 100-fold. DC expansion effects lasted for >35 days. mFlt3L DC were both phenotypically and functionally distinct. They had increased expression of MHC and costimulatory molecules and expressed elevated levels of B220 and DEC205 but had minimal CD4 staining. mFlt3L DC also had a markedly altered cytokine profile, including lowered secretion of IL-6, IL-10, IFN-γ, and TNF-α, but had a slightly increased capacity to stimulate T cells in vitro. However, in a variety of in vivo models, DC expanded by mFlt3L induced tolerogenic effects on T cells. Adoptive transfer of Ag-pulsed mFlt3L splenic DC to naive mice actually caused faster rates of tumor growth and induced minimal CTL compared with control DC. mFlt3L also failed to protect against tumors in which human Flt3 ligand was protective, but depletion of CD4+ T cells restored tumor protection. Our findings 1) demonstrate that mFlt3L has distinct effects on DC development, 2) suggest an important role for mFlt3L in generating DC that have tolerogenic effects on T cells, and 3) may have application in immunotherapy in generating massive numbers of DC for an extended duration.