title: Deletion of Slam locus in mice reveals inhibitory role of SLAM family in NK cell responses regulated by cytokines and LFA-1.
abstract: Signaling lymphocytic activation molecule (SLAM) family receptors (SFRs) can mediate either activating or inhibitory effects during natural killer cell (NK cell) activation. In this study, we addressed the global role, regulation, and mechanism of action of the SLAM family in NK cells by analyzing a mouse lacking the entire ∼400-kilobase Slam locus, which encodes all six SFRs and CD48, the ligand of SFR 2B4. This mouse displayed enhanced NK cell activation responses toward hematopoietic target cells. Analyses of mice lacking individual SFRs showed that the inhibitory function of the Slam locus was due solely to 2B4 and was not influenced positively or negatively by other SFRs. Differences in NK cell responses between recognition of targets expressing or lacking ligands for SFRs were enhanced by IL-12 but suppressed by type I interferon. Cytokines also changed the levels of SLAM-associated protein adaptors, which prevent the inhibitory function of SFRs. The enhanced activation responses of SFR-deficient NK cells were dependent on integrin LFA-1 but not on DNAM-1 or NKG2D. SFR-mediated inhibition prevented the generation of activated forms of LFA-1. Hence, the Slam locus has an overall inhibitory role during NK cell activation that is solely dependent on 2B4. This effect is influenced by cytokines and leads to suppression of LFA-1 activity.
authors: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada Department of Medicine, McGill University, Montréal, Québec H3G 1Y6, Canada.
authors: Huaijian
authors: H
authors: Guo
authors: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors: Stacey A
authors: 0000-0002-7299-3385
authors: SA
authors: Cranert
authors: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors: Yan
authors: Y
authors: Lu
authors: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors: Ming-Chao
authors: 0000-0002-6315-0597
authors: MC
authors: Zhong
authors: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors: Shaohua
authors: S
authors: Zhang
authors: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors: Jun
authors: J
authors: Chen
authors: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada Department of Medicine, McGill University, Montréal, Québec H3G 1Y6, Canada.
authors: Rui
authors: 0000-0002-4803-5339
authors: R
authors: Li
authors: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors: Sarah E
authors: 0000-0002-2872-4524
authors: SE
authors: Mahl
authors: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors: Ning
authors: N
authors: Wu
authors: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors: Dominique
authors: D
authors: Davidson
authors: Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors: Stephen N
authors: SN
authors: Waggoner
authors: Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec H2W 1R7, Canada Department of Medicine, McGill University, Montréal, Québec H3G 1Y6, Canada Department of Medicine, University of Montréal, Montréal, Québec H3T 1J4, Canada veillea@ircm.qc.ca.
authors: André
authors: 0000-0003-1159-4345
authors: A
authors: Veillette
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D017353:Gene Deletion; D056426:Genetic Loci; D006410:Hematopoiesis; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus; D008810:Mice, Inbred C57BL; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000378:metabolism; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1 / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: C490007:Cd244a protein, mouse; D016207:Cytokines; D016169:Lymphocyte Function-Associated Antigen-1; D000071176:Signaling Lymphocytic Activation Molecule Family; C000604062:Slamf1 protein, mouse; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1