INAM plays a critical role in IFN-γ production by NK cells interacting with polyinosinic-polycytidylic acid-stimulated accessory cells

J Immunol. 2014 Nov 15;193(10):5199-207. doi: 10.4049/jimmunol.1400924. Epub 2014 Oct 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8 Antigens / genetics
  • CD8 Antigens / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Differentiation
  • Cell Line, Tumor
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / pathology
  • Gene Expression Regulation
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / pathology
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / pathology
  • Lymphocyte Activation
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / pathology
  • Melanoma, Experimental / genetics*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Mice
  • Mice, Knockout
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Poly I-C / pharmacology*
  • Signal Transduction


  • CD8 Antigens
  • CD8alpha antigen
  • INAM protein, mouse
  • Membrane Glycoproteins
  • Interferon-gamma
  • Poly I-C