Local GM-CSF-Dependent Differentiation and Activation of Pulmonary Dendritic Cells and Macrophages Protect against Progressive Cryptococcal Lung Infection in Mice

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 an...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2016-02, Vol.196 (4), p.1810-1821
Main Authors: Chen, Gwo-Hsiao, Teitz-Tennenbaum, Seagal, Neal, Lori M, Murdock, Benjamin J, Malachowski, Antoni N, Dils, Anthony J, Olszewski, Michal A, Osterholzer, John J
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - immunology
Cryptococcosis - immunology
Cryptococcus neoformans - immunology
Dendritic Cells - immunology
Disease Models, Animal
Flow Cytometry
Fluorescent Antibody Technique
Granulocyte-Macrophage Colony-Stimulating Factor - immunology
Lung Diseases, Fungal - immunology
Macrophage Activation - immunology
Macrophages - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Real-Time Polymerase Chain Reaction
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1501512