title: SHIP1 intrinsically regulates NK cell signaling and education, resulting in tolerance of an MHC class I-mismatched bone marrow graft in mice.
abstract: NK cells are an important component of host immune defense against malignancy and infection. NK cells are educated by MHC class I ligands to ensure self-tolerance while also promoting lytic competency against altered self and damaged self targets. However, the intracellular molecular events that culminate in tolerance and functional competency of educated NK cells remain undefined. Mice with germline deficiency in SHIP1 were shown to have a defective NK cell compartment. However, SHIP1 is expressed in all hematopoietic lineages, and consequently several hematolymphoid phenotypes have already been identified in certain cell types that are the result of SHIP1 deficiency in cells in separate and distinct lineages, that is, cell-extrinsic phenotypes. Thus, it was previously impossible to determine the NK cell-intrinsic role of SHIP1. In the present study, through the creation of an NK cell-specific deletion mouse model of SHIP1, we show that SHIP1 plays a profound NK lineage-intrinsic role in NK cell homeostasis, development, education, and cytokine production. Moreover, we show SHIP1 expression by NK cells is required for in vivo-mismatched bone marrow allograft rejection as well as for NK memory responses to hapten.
authors: Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210;
authors: Matthew
authors: M
authors: Gumbleton
authors: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University Unité Mixte 2, 13288 Marseille, France; INSERM Unité 1104, 13288 Marseille, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 7280, 13288 Marseille, France; Service d'Immunologie, Assistance Publique-Hôpitaux de Marseille, Hôpital de la Conception, 13385 Marseille, France;
authors: Eric
authors: E
authors: Vivier
authors: Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210; Department of Pediatrics, State University of New York Upstate Medical University, Syracuse, NY 13210; and Department of Chemistry, Syracuse University, Syracuse, NY 13210 KerrW@upstate.edu.
authors: William G
authors: http://orcid.org/0000-0002-4720-7135
authors: WG
authors: Kerr
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006241:Haptens / Q000276:immunology; D006648:Histocompatibility / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D000072181:Inositol Polyphosphate 5-Phosphatases; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000276:immunology / Q000378:metabolism; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D006241:Haptens; D015395:Histocompatibility Antigens Class I; C527092:Klra4 protein, mouse; C527086:Klrk1 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A; D051920:NK Cell Lectin-Like Receptor Subfamily D; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D007371:Interferon-gamma; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases