title: Interleukin-17A enhances host defense against cryptococcal lung infection through effects mediated by leukocyte recruitment, activation, and gamma interferon production.
abstract: Infection of C57BL/6 mice with the moderately virulent Cryptococcus neoformans strain 52D models the complex adaptive immune response observed in HIV-negative patients with persistent fungal lung infections. In this model, Th1 and Th2 responses evolve over time, yet the contribution of interleukin-17A (IL-17A) to antifungal host defense is unknown. In this study, we show that fungal lung infection promoted an increase in Th17 T cells that persisted to 8 weeks postinfection. Our comparison of fungal lung infection in wild-type mice and IL-17A-deficient mice (IL-17A(-/-) mice; C57BL/6 genetic background) demonstrated that late fungal clearance was impaired in the absence of IL-17A. This finding was associated with reduced intracellular containment of the organism within lung macrophages and deficits in the accumulation of total lung leukocytes, including specific reductions in CD11c+ CD11b+ myeloid cells (dendritic cells and exudate macrophages), B cells, and CD8+ T cells, and a nonsignificant trend in the reduction of lung neutrophils. Although IL-17A did not alter the total number of CD4 T cells, decreases in the total number of CD4 T cells and CD8 T cells expressing gamma interferon (IFN-γ) were observed in IL-17A(-/-) mice. Lastly, expression of major histocompatibility complex class II (MHC-II) and the costimulatory molecules CD80 and CD86 on CD11c+ CD11b+ myeloid cells was diminished in IL-17A(-/-) mice. Collectively, these data indicate that IL-17A enhances host defenses against a moderately virulent strain of C. neoformans through effects on leukocyte recruitment, IFN-γ production by CD4 and CD8 T cells, and the activation of lung myeloid cells.
authors: Pulmonary Section, VA Ann Arbor Healthcare System, Michigan, USA.
authors: Benjamin J
authors: BJ
authors: Murdock
authors: Gary B
authors: GB
authors: Huffnagle
authors: Michal A
authors: MA
authors: Olszewski
authors: John J
authors: JJ
authors: Osterholzer
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000382:microbiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D003453:Cryptococcosis / Q000276:immunology / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D007371:Interferon-gamma / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology* / Q000382:microbiology; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology / Q000382:microbiology; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology; D018417:Th1 Cells / Q000276:immunology / Q000382:microbiology; D018418:Th2 Cells / Q000276:immunology / Q000382:microbiology
chemical_list: D015703:Antigens, CD; D020381:Interleukin-17; D007371:Interferon-gamma