Overexpression of interleukin-12 enables dendritic cells to activate NK cells and confer systemic antitumor immunity.
Dendritic cells (DC) are initiators of T cell-mediated immunity. However, less is known about the relationship between DC and natural killer (NK) cells, and direct evidence of their interaction in vivo is scarce. Interleukin (IL)-12 is an activator of both DC and NK cells. We postulated that secretion of IL-12 by DC would enable them to activate NK cells. Bone marrow-derived DC propagated only in granulocyte macrophage colony-stimulating factor did not activate NK cells. In contrast, DC engineered to express IL-12 markedly stimulated NK cells as determined by coculture experiments in vitro, assays of NK cells isolated from treated animals, and survival experiments in a systemic tumor model. Activation depended on both DC-NK cellular interaction and secretion of IL-12. Adoptive transfer of DC expressing IL-12 to mice markedly increased NK cell interferon-gamma production and lytic activity in vivo. Treated mice were also protected against B16 melanoma hepatic metastases. The in vivo effects on NK cells were DC-specific. Administration of IL-12 protein alone or melanoma cells or fibroblasts engineered to secrete IL-12 were only weakly activating. Our findings demonstrate that IL-12 expression by DC enables them to activate NK cells and provide evidence for a substantial DC-NK relationship in vivo.
Miller
George
G
Hepatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Lahrs
Svenja
S
Dematteo
Ronald P
RP
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D007376:Interleukin-2