title: Intracellular osteopontin regulates homeostasis and function of natural killer cells.
abstract: Natural killer (NK) cells play an essential role in the immune response to infection and cancer. After infection or during homeostatic expansion NK cells express a developmental program that includes a contraction phase followed by the formation of long-lived mature memory-like cells. Although this NK cell response pattern is well established, the underlying mechanisms that ensure efficient transition to long-lived NK cells remain largely undefined. Here we report that deficient expression of intracellular osteopontin (OPN-i) by NK cells results in defective responses to IL-15 associated with a substantial increase in the NK cell contraction phase of homeostatic expansion, defective expression of the Eomes transcription factor, and diminished responses to metastatic tumors. The OPN-i-deficient phenotype is accompanied by increased NK cell apoptosis, impaired transition from immature to mature NK cells, and diminished ability to develop memory-like NK cells that respond to mouse cytomegalovirus. Gene pathway analysis of OPN-i-deficient NK cells suggests that the mechanistic target of rapamycin pathway may connect OPN-i to Eomes and T-bet expression by mature NK cells following up-regulation of OPN-i after IL-15 stimulation. Identification of OPN-i as an essential molecular component for maintenance of functional NK cell expansion provides insight into the NK cell response and may provide the basis for improved approaches to immunotherapy for infectious disease and cancer.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA 02115;
authors.forename: Jianmei W
authors.initials: JW
authors.lastname: Leavenworth
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and.
authors.forename: Bert
authors.initials: B
authors.lastname: Verbinnen
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Immunology, Medical College of Soochow University, Suzhou, Jiangsu 215123, China; and.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Pathogenic Biology and Immunology, Guangzhou Hoffmann Institute of Immunology, School of Basic Sciences, Guangzhou Medical University, Guangzhou 510182, China.
authors.forename: Erxia
authors.initials: E
authors.lastname: Shen
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA 02115; harvey_cantor@dfci.harvard.edu.
authors.forename: Harvey
authors.initials: H
authors.lastname: Cantor
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D006706:Homeostasis / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D008546:Melanoma, Experimental / Q000276:immunology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: C491198:Eomes protein, mouse; D019409:Interleukin-15; C506896:Spp1 protein, mouse; D020825:T-Box Domain Proteins; D053495:Osteopontin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: T-box transcription factor; cellular maintenance; contraction; long-lived cell; memory cell