title: Neither classical nor alternative macrophage activation is required for Pneumocystis clearance during immune reconstitution inflammatory syndrome.
abstract: Pneumocystis is a respiratory fungal pathogen that causes pneumonia (Pneumocystis pneumonia [PcP]) in immunocompromised patients. Alveolar macrophages are critical effectors for CD4(+) T cell-dependent clearance of Pneumocystis, and previous studies found that alternative macrophage activation accelerates fungal clearance during PcP-related immune reconstitution inflammatory syndrome (IRIS). However, the requirement for either classically or alternatively activated macrophages for Pneumocystis clearance has not been determined. Therefore, RAG2(-/-) mice lacking either the interferon gamma (IFN-γ) receptor (IFN-γR) or interleukin 4 receptor alpha (IL-4Rα) were infected with Pneumocystis. These mice were then immune reconstituted with wild-type lymphocytes to preserve the normal T helper response while preventing downstream effects of Th1 or Th2 effector cytokines on macrophage polarization. As expected, RAG2(-/-) mice developed severe disease but effectively cleared Pneumocystis and resolved IRIS. Neither RAG/IFN-γR(-/-) nor RAG/IL-4Rα(-/-) mice displayed impaired Pneumocystis clearance. However, RAG/IFN-γR(-/-) mice developed a dysregulated immune response, with exacerbated IRIS and greater pulmonary function deficits than those in RAG2 and RAG/IL-4Rα(-/-) mice. RAG/IFN-γR(-/-) mice had elevated numbers of lung CD4(+) T cells, neutrophils, eosinophils, and NK cells but severely depressed numbers of lung CD8(+) T suppressor cells. Impaired lung CD8(+) T cell responses in RAG/IFN-γR(-/-) mice were associated with elevated lung IFN-γ levels, and neutralization of IFN-γ restored the CD8 response. These data demonstrate that restricting the ability of macrophages to polarize in response to Th1 or Th2 cytokines does not impair Pneumocystis clearance. However, a cell type-specific IFN-γ/IFN-γR-dependent mechanism regulates CD8(+) T suppressor cell recruitment, limits immunopathogenesis, preserves lung function, and enhances the resolution of PcP-related IRIS.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Zhuo-Qian
authors.initials: ZQ
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Hoy
authors.affiliation: Center for Vascular and Inflammatory Diseases, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Achsah
authors.initials: A
authors.lastname: Keegan
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Bhagwat
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Gigliotti
authors.affiliation: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA Terry_Wright@urmc.rochester.edu.
authors.forename: Terry W
authors.initials: TW
authors.lastname: Wright
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D004804:Eosinophils / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D054019:Immune Reconstitution Inflammatory Syndrome / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D011010:Pneumocystis / Q000276:immunology* / Q000472:pathogenicity; D011020:Pneumonia, Pneumocystis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D058408:Th1-Th2 Balance; D000096743:Interferon gamma Receptor; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D004268:DNA-Binding Proteins; D011956:Receptors, Cell Surface; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C499308:Rag2 protein, mouse