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Therefore, Pneumocystis-infected immunodeficient mice were immune reconstituted and administered control or anti\u2013IFN-\u03b3 neutralizing Ab to determine how IFN-\u03b3 regulates the balance between host defense and immune-mediated lung injury. Mice treated with anti\u2013IFN-\u03b3 demonstrated an initial worsening of Pneumocystis pneumonia\u2013related immunopathogenesis, with greater weight loss, heightened lung inflammation, and more severe pulmonary function deficits than control mice. However, IFN-\u03b3 neutralization also enhanced macrophage phagocytosis of Pneumocystis and accelerated fungal clearance. When anti\u2013IFN-\u03b3\u2013treated mice were also given IL-4 and IL-13 to promote a Th2-biased lung environment, the accelerated fungal clearance was preserved, but the severity of immunopathogenesis was reduced, and a more rapid recovery was observed. A direct suppressive effect of IFN-\u03b3 on macrophages was required but was not solely responsible for delayed fungal clearance, suggesting that IFN-\u03b3 acts through multiple mechanisms that likely include modulation of both macrophage and Th polarization. Enhanced Pneumocystis clearance in anti\u2013IFN-\u03b3\u2013treated and IFN-\u03b3R\u2013deficient mice was associated with significantly elevated IL-17+ CD4+ T cells and IL-17 protein in the lungs. Furthermore, neutralization of IL-17, but not IL-4, signaling blocked the accelerated fungal clearance observed in anti\u2013IFN-\u03b3\u2013treated mice. Together, these data demonstrate that although IFN-\u03b3 delays fungal clearance by suppressing the lung Th17 response, it also serves an important regulatory role that limits immunopathogenesis and preserves pulmonary function.<\/jats:p>","DOI":"10.4049\/jimmunol.2300460","type":"journal-article","created":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T12:36:02Z","timestamp":1695040562000},"page":"1397-1405","source":"Crossref","is-referenced-by-count":10,"title":["IFN-\u03b3 Limits Immunopathogenesis but Delays Fungal Clearance during <i>Pneumocystis<\/i> Pneumonia"],"prefix":"10.1093","volume":"211","author":[{"given":"Jing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Rochester School of Medicine and Dentistry , Rochester, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuo-Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry , Rochester, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francis","family":"Gigliotti","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Rochester School of Medicine and Dentistry , Rochester, NY"},{"name":"Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry , Rochester, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terry W","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Rochester School of Medicine and Dentistry , Rochester, NY"},{"name":"Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry , Rochester, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,9,18]]},"reference":[{"key":"2025020406171832800_r1","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1086\/320164","article-title":"Changing spectrum of mortality due to human immunodeficiency virus: analysis of 260 deaths during 1995\u20131999","volume":"32","author":"Valdez","year":"2001","journal-title":"Clin. 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