title: Role of IFN-gamma in regulating T2 immunity and the development of alternatively activated macrophages during allergic bronchopulmonary mycosis.
abstract: Pulmonary Cryptococcus neoformans infection of C57BL/6 mice is an established model of a chronic pulmonary fungal infection accompanied by an "allergic" response (T2) to the infection, i.e., a model of an allergic bronchopulmonary mycosis. Our objective was to determine whether IFN-gamma plays a role in regulating the pulmonary T2 immune response in C. neoformans-infected C57BL/6 mice. Long-term pulmonary fungistasis was lost in IFN-gamma knockout (KO) mice, resulting in an increased pulmonary burden of fungi at wk 3. IFN-gamma was required for the early influx of leukocytes into the lungs but was not required later in the infection. By wk 3, eosinophil and macrophage numbers were elevated in the absence of IFN-gamma. The inducible NO synthase to arginase ratio was lower in the lungs of IFN-gamma KO mice and the macrophages had increased numbers of intracellular cryptococci and YM1 crystals, indicative of alternatively activated macrophages in these mice. There was evidence of pulmonary fibrosis in both wild-type and IFN-gamma KO mice by 5 wk postinfection. IFN-gamma production was not required for the development of T2 cytokine (IL-4, IL-5, IL-13) producing cells in the lungs and lung-associated lymph nodes or induction of an IgE response. At a number of time points, T2 cytokine production was enhanced in IFN-gamma KO mice. Thus, in the absence of IFN-gamma, C57BL/6 mice develop an augmented allergic response to C. neoformans, including enhanced generation of alternatively activated macrophages, which is accompanied by a switch from a chronic to a progressive pulmonary cryptococcal infection.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Shikha
authors.initials: S
authors.lastname: Arora
authors.forename: Yadira
authors.initials: Y
authors.lastname: Hernandez
authors.forename: John R
authors.initials: JR
authors.lastname: Erb-Downward
authors.forename: Roderick A
authors.initials: RA
authors.lastname: McDonald
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Gary B
authors.initials: GB
authors.lastname: Huffnagle
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D003453:Cryptococcosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D003455:Cryptococcus neoformans / Q000254:growth & development / Q000276:immunology; D005260:Female; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000097:blood; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D037102:Lectins / Q000096:biosynthesis; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008174:Lung Diseases, Parasitic / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000096:biosynthesis
chemical_list: D018836:Inflammation Mediators; D037102:Lectins; D007073:Immunoglobulin E; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases; D001119:Arginase