title: NK-cell-mediated killing of target cells triggers robust antigen-specific T-cell-mediated and humoral responses.
abstract: Previous work showed that administration of antigen-expressing apoptotic cells in vivo results in antigen-specific CD8+ T-cell responses independent of Toll-like receptor signaling. We report here that natural killer (NK) cells can serve a function directly upstream of this pathway and initiate robust adaptive immune responses via killing of antigen-expressing target cells. This pathway is highly sensitive, in that administration of as few as 10(4) target cells induced detectable antigen-specific CD8+ T-cell responses. Importantly, NK cell-mediated cytotoxicity of target cells could also induce robust antigen-specific CD4+ T-cell responses, which were critical for subsequent CD8+ T-cell priming and IgG responses. Unlike adaptive immune responses induced by gamma-irradiated cells, the NK-cell pathway required myeloid differentiating factor 88 (MyD88) and Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-beta (Trif) signaling. NK cells have previously been shown to detect and kill pathogen-infected host cells, as well as neoplastic cells and tissue allografts. The present data provide further evidence that they also discharge a strong tie with their relatives in the adaptive immune system. We think that the recognition and killing of target cells by NK cells represents an important pathway for the generation of robust CD8+ T and humoral responses that may be exploited for vaccine development.
authors.affiliation: Department of Genetics, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA. pkrebs@scripps.edu
authors.forename: Philippe
authors.initials: P
authors.lastname: Krebs
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Barnes
authors.forename: Kristin
authors.initials: K
authors.lastname: Lampe
authors.forename: Karen
authors.initials: K
authors.lastname: Whitley
authors.forename: Keith S
authors.initials: KS
authors.lastname: Bahjat
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.forename: Edith
authors.initials: E
authors.lastname: Janssen
authors.forename: Kasper
authors.initials: K
authors.lastname: Hoebe
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000502:physiology; D000818:Animals; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006183:H-2 Antigens / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007156:Immunologic Memory; D007694:Killer Cells, Natural / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000502:physiology; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity; D014611:Vaccination
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D006183:H-2 Antigens; D007074:Immunoglobulin G; D053594:Myeloid Differentiation Factor 88; D010047:Ovalbumin; D010446:Peptide Fragments; C032876:H-2Kb protein, mouse; C507780:Myd88 protein, mouse; C111390:OVA 323-339; C110366:OVA-8; C476286:Ticam1 protein, mouse