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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 \u223c400-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.<\/jats:p>","DOI":"10.1084\/jem.20160552","type":"journal-article","created":{"date-parts":[[2016,8,29]],"date-time":"2016-08-29T10:07:24Z","timestamp":1472465244000},"page":"2187-2207","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Deletion of\n                    <i>Slam<\/i>\n                    locus in mice reveals inhibitory role of SLAM family in NK cell responses regulated by cytokines and LFA-1"],"prefix":"10.1084","volume":"213","author":[{"given":"Huaijian","family":"Guo","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Oncology, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec H2W 1R7, Canada 1"},{"name":"Department of Medicine, McGill University, Montr\u00e9al, Qu\u00e9bec H3G 1Y6, Canada 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7299-3385","authenticated-orcid":false,"given":"Stacey A.","family":"Cranert","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec H2W 1R7, Canada 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6315-0597","authenticated-orcid":false,"given":"Ming-Chao","family":"Zhong","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec H2W 1R7, Canada 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaohua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec H2W 1R7, Canada 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec H2W 1R7, Canada 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4803-5339","authenticated-orcid":false,"given":"Rui","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec H2W 1R7, Canada 1"},{"name":"Department of Medicine, McGill University, Montr\u00e9al, Qu\u00e9bec H3G 1Y6, Canada 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2872-4524","authenticated-orcid":false,"given":"Sarah E.","family":"Mahl","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Wu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec H2W 1R7, Canada 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Davidson","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec H2W 1R7, Canada 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen N.","family":"Waggoner","sequence":"additional","affiliation":[{"name":"Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1159-4345","authenticated-orcid":false,"given":"Andr\u00e9","family":"Veillette","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, Institut de recherches cliniques de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec H2W 1R7, Canada 1"},{"name":"Department of Medicine, McGill University, Montr\u00e9al, Qu\u00e9bec H3G 1Y6, Canada 2"},{"name":"Department of Medicine, University of Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec H3T 1J4, Canada 4"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,8,29]]},"reference":[{"key":"2023072603154377600_bib1","doi-asserted-by":"publisher","first-page":"3653","DOI":"10.4049\/jimmunol.173.6.3653","article-title":"LFA-1 contributes an early signal for NK cell cytotoxicity","volume":"173","author":"Barber","year":"2004","journal-title":"J. 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