title: Ly49 family receptors are required for cancer immunosurveillance mediated by natural killer cells.
abstract: According to the missing-self hypothesis, natural killer (NK) cells survey for target cells that lack MHC-I molecules. The Ly49 receptor family recognizes loss of MHC-I and is critical for educating NK cells, conferring the ability to eliminate transformed or infected cells. In this study, we evaluated their requirement in innate immune surveillance of cancer cells using genetically manipulated mice with attenuated expression of Ly49 receptors (NKC(KD)) in several models of carcinoma and metastasis. We found that NKC(KD) mice exhibited uncontrolled tumor growth and metastases. Expression of two MHC-I alleles, H-2K(b) and H-2D(b), was decreased in tumors from NKC(KD) mice in support of the likelihood of NK-mediated tumor immunoediting. These tumor cells exhibited directed alterations to their cell surface expression in response to the genetically altered immune environment to evade host recognition. Immunoediting in NKC(KD) mice was restricted to MHC-I molecules, which are ligands for Ly49 receptors, while expression of Rae-1 and Mult1, ligands for another NK cell receptor, NKG2D, were unaffected. Restoring NK cell education in NKC(KD) mice with a transgene for the inhibitory self-MHC-I receptor Ly49I restored suppression of cancer onset and growth. Interestingly, immune surveillance mediated by activating Ly49 receptors remained intact in NKC(KD) mice, as demonstrated by the ability to stimulate the NKG2D receptor with tumor cells or splenocytes expressing Rae-1. Together, our results genetically establish the integral role of Ly49 in NK cell-mediated control of carcinogenesis through MHC-I-dependent missing-self recognition.
authors.affiliation: Authors' Affiliations: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario;
authors.forename: Megan M
authors.initials: MM
authors.lastname: Tu
authors.affiliation: Authors' Affiliations: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario; College of Applied Medical Sciences, Taibah University, Madinah Munawwarah, Saudi Arabia.
authors.forename: Ahmad Bakur
authors.initials: AB
authors.lastname: Mahmoud
authors.affiliation: Authors' Affiliations: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario;
authors.forename: Andrew
authors.initials: A
authors.lastname: Wight
authors.affiliation: Authors' Affiliations: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario;
authors.forename: Amelia
authors.initials: A
authors.lastname: Mottashed
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada; and.
authors.forename: Simon
authors.initials: S
authors.lastname: Bélanger
authors.affiliation: Authors' Affiliations: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario;
authors.forename: Mir Munir A
authors.initials: MM
authors.lastname: Rahim
authors.affiliation: Authors' Affiliations: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario;
authors.forename: Elias
authors.initials: E
authors.lastname: Abou-Samra
authors.affiliation: Authors' Affiliations: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario; amakrigi@uottawa.ca.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Makrigiannis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D007157:Immunologic Surveillance; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D047368:Tumor Burden
chemical_list: D015395:Histocompatibility Antigens Class I; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D007371:Interferon-gamma