title: Role of SHIP1 in Invariant NKT Cell Development and Functions.
abstract: SHIP1 is a 5'-inositol phosphatase known to negatively regulate the signaling product of the PI3K pathway, phosphatidylinositol (3-5)-trisphosphate. SHIP1 is recruited to a large number of inhibitory receptors expressed on invariant NK (iNKT) cells. We hypothesized that SHIP1 deletion would have major effects on iNKT cell development by altering the thresholds for positive and negative selection. Germline SHIP1 deletion has been shown to affect T cells as well as other immune cell populations. However, the role of SHIP1 on T cell function has been controversial, and its participation on iNKT cell development and function has not been examined. We evaluated the consequences of SHIP1 deletion on iNKT cells using germline-deficient mice, chimeric mice, and conditionally deficient mice. We found that T cell and iNKT cell development are impaired in germline-deficient animals. However, this phenotype can be rescued by extrinsic expression of SHIP1. In contrast, SHIP1 is required cell autonomously for optimal iNKT cell cytokine secretion. This suggests that SHIP1 calibrates the threshold of iNKT cell reactivity. These data further our understanding of how iNKT cell activation is regulated and provide insights into the biology of this unique cell lineage.
authors.affiliation: Department of Molecular Microbiology & Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912.
authors.forename: Courtney K
authors.initials: CK
authors.lastname: Anderson
authors.affiliation: Department of Molecular Microbiology & Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Salter
authors.affiliation: Department of Molecular Microbiology & Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912.
authors.forename: Leon E
authors.initials: LE
authors.lastname: Toussaint
authors.affiliation: Department of Molecular Microbiology & Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Reilly
authors.affiliation: Department of Molecular Microbiology & Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912.
authors.forename: Céline
authors.initials: C
authors.lastname: Fugère
authors.affiliation: Departments of Pediatrics and Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210.
authors.forename: Neetu
authors.initials: N
authors.lastname: Srivastava
authors.affiliation: Departments of Pediatrics and Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210.|Chemistry Department, Syracuse University, Syracuse, NY 13210.
authors.forename: William G
authors.initials: WG
authors.lastname: Kerr
authors.affiliation: Department of Molecular Microbiology & Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912.
authors.forename: Laurent
authors.initials: L
authors.lastname: Brossay
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation / Q000379:methods; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D000072181:Inositol Polyphosphate 5-Phosphatases; D008099:Liver / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases