title: Fas regulates neutrophil lifespan during viral and bacterial infection.
abstract: The regulation of neutrophil lifespan is critical for a circumscribed immune response. Neutrophils are sensitive to Fas/CD95 death receptor signaling in vitro, but it is unknown if Fas regulates neutrophil lifespan in vivo. We hypothesized that FasL-expressing CD8(+) T cells, which kill antigen-stimulated T cells during chronic viral infection, can also induce neutrophil death in tissues during infection. With the use of LysM-Cre Fas(fl/fl) mice, which lack Fas expression in macrophages and neutrophils, we show that Fas regulates neutrophil lifespan during lymphocytic choriomeningitis virus (LCMV) infection in the lung, peripheral blood, and spleen. Fas also contributed to the regulation of neutrophil numbers in the colon of Citrobacter rodentium-infected mice. To examine the effects of infection on Fas activation in neutrophils, we primed neutrophils with TLR ligands or IL-18, resulting in ablation of Fas death receptor signaling. These data provide the first in vivo genetic evidence that neutrophil lifespan is controlled by death receptor signaling and provide a mechanism to account for neutrophil resistance to Fas stimulation during infection.
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Joanne A
authors.initials: JA
authors.lastname: O'Donnell
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Kennedy
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Nowell
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Louise
authors.initials: L
authors.lastname: Cengia
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Stuart
authors.initials: S
authors.lastname: Dias
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Hartland
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Motti
authors.initials: M
authors.lastname: Gerlic
authors.affiliation: *Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology and Faculty of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; and Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel ben.croker@childrens.harvard.edu.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Croker
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology*; D044082:Citrobacter rodentium / Q000276:immunology*; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
chemical_list: D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; D020382:Interleukin-18; D019014:fas Receptor
keywords: Citrobacter rodentium; IL-18; LCMV; TLR; apoptosis