ABSTRACT
Dendritic cells (DCs) are critical in initiating immune responses by cross-priming of tumor Ags to T cells. Previous results showed that NK cells inhibited DC-mediated cross-presentation of tumor Ags both in vivo and in vitro. In this study, enhanced Ag presentation was observed in draining lymph nodes in TRAIL(-/-) and DR5(-/-) mice compared with that of wild-type mice. NK cells inhibit DC cross-priming of tumor Ags in vitro, but not direct presentation of endogenous Ags. NK cells lacking TRAIL, but not perforin, were not able to inhibit DC cross-priming of tumor Ags. DCs that lack expression of TRAIL receptor DR5 were less susceptible to NK cell-mediated inhibition of cross-priming, and cross-linking of DR5 receptor led to reduced generation of MHC class I-Ag peptide complexes, followed by attenuated cross-priming of CD8(+) T cells. In addition, key molecules involved in the TRAIL/DR5 pathway during DC/NK cell interactions were determined. In summary, these data indicate a novel alternative pathway for DC/NK cell interactions in antitumor immunity and may reflect homeostasis of both DCs and NK cells for regulation of CD8(+) T cell function in physiological conditions.
Subject(s)
Cross-Priming/immunology , Dendritic Cells/immunology , Killer Cells, Natural/immunology , Receptors, TNF-Related Apoptosis-Inducing Ligand/immunology , T-Lymphocytes/immunology , TNF-Related Apoptosis-Inducing Ligand/immunology , Animals , Antigen Presentation/immunology , Cell Separation , Dendritic Cells/metabolism , Flow Cytometry , Killer Cells, Natural/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/metabolismABSTRACT
BACKGROUND: NK cell activity is regulated in part by inhibitory receptors that bind to MHC class I molecules. It is possible to enhance NK cell cytotoxicity against tumor cells by preventing the interaction of these inhibitory receptors with their MHC class I ligands. RESULTS: In this study, we determined that Ly49G2 is an inhibitory receptor in AKR mice for self-MHC class I, and AKR Ly49G2 has an identical sequence to BALB/c Ly49G2. Blockade of Ly49G2 receptors in vivo resulted in decreased growth of BW-Sp3 lymphoma cells when the tumor cells were given i.v. but not when the tumor cells were inoculated into the flank forming a solid tumor. However, NK cells were involved in inhibiting the growth of BW-Sp3 tumor cells in the flank. CONCLUSION: These data demonstrate that the effectiveness of inhibitory receptor blockade depends upon the tissue location of the tumor cells.
Subject(s)
Killer Cells, Natural/immunology , Lectins, C-Type/antagonists & inhibitors , Leukemia/therapy , Neoplasms, Experimental/therapy , Animals , Antigens, Ly/genetics , Base Sequence , Disease Models, Animal , Flow Cytometry , Lectins, C-Type/genetics , Leukemia/immunology , Mice , Molecular Sequence Data , Neoplasms, Experimental/immunology , Receptors, NK Cell Lectin-Like , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
NK cells are known to kill tumor cells and produce proinflammatory cytokines that lead to the generation of tumor-specific CTLs. Many studies have used MHC class I-deficient tumor cells and/or adjuvants that induce NK cell responses. In this study, the focus was on less-immunogenic lymphoma cells that express MHC class I as a model to study NK cell responses to tumors that do not directly stimulate NK cell activation. When RMA tumor cells that expressed a truncated version of OVA, or RMA cells alone, were injected into mice that were depleted of NK cells, the mice developed an increased number of tumor-specific CTLs, increased IFN-gamma responses, and a higher amount of Ag presentation in draining LNs compared with mice with intact NK cells. These data suggest that NK cells can inhibit the development of effective adaptive immunity in the absence of signals that trigger NK cell activation.