title: Local GM-CSF-Dependent Differentiation and Activation of Pulmonary Dendritic Cells and Macrophages Protect against Progressive Cryptococcal Lung Infection in Mice.
abstract: Patients with acquired deficiency in GM-CSF are susceptible to infections with Cryptococcus neoformans and other opportunistic fungi. We previously showed that GM-CSF protects against progressive fungal disease using a murine model of cryptococcal lung infection. To better understand the cellular and molecular mechanisms through which GM-CSF enhances antifungal host defenses, we investigated temporal and spatial relationships between myeloid and lymphoid immune responses in wild-type C57BL/6 mice capable of producing GM-CSF and GM-CSF-deficient mice infected with a moderately virulent encapsulated strain of C. neoformans (strain 52D). Our data demonstrate that GM-CSF deficiency led to a reduction in: 1) total lung leukocyte recruitment; 2) Th2 and Th17 responses; 3) total numbers of CD11b(+) dendritic cells (DC) and CD11b(-) and CD11b(+) macrophages (Mϕ); 4) DC and Mϕ activation; and 5) localization of DC and Mϕ to the microanatomic sites of alveolar infection. In contrast, GM-CSF deficiency resulted in increased accumulation of DC and Mϕ precursors, namely Ly-6C(high) monocytes, in the blood and lungs of infected mice. Collectively, these results show that GM-CSF promotes the local differentiation, accumulation, activation, and alveolar localization of lung DC and Mϕ in mice with cryptococcal lung infection. These findings identify GM-CSF as central to the protective immune response that prevents progressive fungal disease and thus shed new light on the increased susceptibility to these infections observed in patients with acquired GM-CSF deficiency.
authors.affiliation: Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Gwo-Hsiao
authors.initials: GH
authors.lastname: Chen
authors.affiliation: Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Seagal
authors.initials: S
authors.lastname: Teitz-Tennenbaum
authors.affiliation: Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Lori M
authors.initials: LM
authors.lastname: Neal
authors.affiliation: Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Murdock
authors.affiliation: Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Antoni N
authors.initials: AN
authors.lastname: Malachowski
authors.affiliation: Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Dils
authors.affiliation: Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; Graduate Program in Immunology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; and.
authors.forename: Michal A
authors.initials: MA
authors.lastname: Olszewski
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; Graduate Program in Immunology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; and Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105 oster@umich.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Osterholzer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D003453:Cryptococcosis / Q000276:immunology*; D003455:Cryptococcus neoformans / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D008172:Lung Diseases, Fungal / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor