title: Activation by SLAM Family Receptors Contributes to NK Cell Mediated "Missing-Self" Recognition.
abstract: Natural Killer (NK) cells attack normal hematopoietic cells that do not express inhibitory MHC class I (MHC-I) molecules, but the ligands that activate NK cells remain incompletely defined. Here we show that the expression of the Signaling Lymphocyte Activation Molecule (SLAM) family members CD48 and Ly9 (CD229) by MHC-I-deficient tumor cells significantly contributes to NK cell activation. When NK cells develop in the presence of T cells or B cells that lack inhibitory MHC-I but express activating CD48 and Ly9 ligands, the NK cells' ability to respond to MHC-I-deficient tumor cells is severely compromised. In this situation, NK cells express normal levels of the corresponding activation receptors 2B4 (CD244) and Ly9 but these receptors are non-functional. This provides a partial explanation for the tolerance of NK cells to MHC-I-deficient cells in vivo. Activating signaling via 2B4 is restored when MHC-I-deficient T cells are removed, indicating that interactions with MHC-I-deficient T cells dominantly, but not permanently, impair the function of the 2B4 NK cell activation receptor. These data identify an important role of SLAM family receptors for NK cell mediated "missing-self" reactivity and suggest that NK cell tolerance in MHC-I mosaic mice is in part explained by an acquired dysfunction of SLAM family receptors.
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Epalinges, Switzerland.
authors.forename: Elisenda
authors.initials: E
authors.lastname: Alari-Pahissa
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Epalinges, Switzerland.
authors.forename: Camille
authors.initials: C
authors.lastname: Grandclément
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Epalinges, Switzerland.
authors.forename: Beena
authors.initials: B
authors.lastname: Jeevan-Raj
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, University of Ghent, Ghent, Belgium.
authors.forename: Georges
authors.initials: G
authors.lastname: Leclercq
authors.affiliation: Department of Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Veillette
authors.affiliation: Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Epalinges, Switzerland.
authors.forename: Werner
authors.initials: W
authors.lastname: Held
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D000071176:Signaling Lymphocytic Activation Molecule Family; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; C490007:Cd244a protein, mouse; D015395:Histocompatibility Antigens Class I; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1