title: INAM plays a critical role in IFN-γ production by NK cells interacting with polyinosinic-polycytidylic acid-stimulated accessory cells.
abstract: Polyinosinic-polycytidylic acid strongly promotes the antitumor activity of NK cells via TLR3/Toll/IL-1R domain-containing adaptor molecule 1 and melanoma differentiation-associated protein-5/mitochondrial antiviral signaling protein pathways. Polyinosinic-polycytidylic acid acts on accessory cells such as dendritic cells (DCs) and macrophages (Mφs) to secondarily activate NK cells. In a previous study in this context, we identified a novel NK-activating molecule, named IFN regulatory factor 3-dependent NK-activating molecule (INAM), a tetraspanin-like membrane glycoprotein (also called Fam26F). In the current study, we generated INAM-deficient mice and investigated the in vivo function of INAM. We found that cytotoxicity against NK cell-sensitive tumor cell lines was barely decreased in Inam(-/-) mice, whereas the number of IFN-γ-producing cells was markedly decreased in the early phase. Notably, deficiency of INAM in NK and accessory cells, such as CD8α(+) conventional DCs and Mφs, led to a robust decrease in IFN-γ production. In conformity with this phenotype, INAM effectively suppressed lung metastasis of B16F10 melanoma cells, which is controlled by NK1.1(+) cells and IFN-γ. These results suggest that INAM plays a critical role in NK-CD8α(+) conventional DC (and Mφ) interaction leading to IFN-γ production from NK cells in vivo. INAM could therefore be a novel target molecule for cancer immunotherapy against IFN-γ-suppressible metastasis.
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan;
authors.forename: Jun
authors.initials: J
authors.lastname: Kasamatsu
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan;
authors.forename: Masahiro
authors.initials: M
authors.lastname: Azuma
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Oshiumi
authors.affiliation: Division of Disease Model Innovation, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-8638, Japan;
authors.forename: Yuka
authors.initials: Y
authors.lastname: Morioka
authors.affiliation: Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Okabe
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Ebihara
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan;
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan; seya-tu@pop.med.hokudai.ac.jp.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011070:Poly I-C / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D016827:CD8 Antigens; C431698:CD8alpha antigen; C000595458:INAM protein, mouse; D008562:Membrane Glycoproteins; D007371:Interferon-gamma; D011070:Poly I-C