{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T21:17:10Z","timestamp":1790371030199,"version":"4.1.0"},"reference-count":41,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p><jats:named-content content-type=\"genus-species\">Pneumocystis<\/jats:named-content>is a respiratory fungal pathogen that causes pneumonia (<jats:named-content content-type=\"genus-species\">Pneumocystis<\/jats:named-content>pneumonia [PcP]) in immunocompromised patients. Alveolar macrophages are critical effectors for CD4<jats:sup>+<\/jats:sup>T cell-dependent clearance of<jats:named-content content-type=\"genus-species\">Pneumocystis<\/jats:named-content>, 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<jats:named-content content-type=\"genus-species\">Pneumocystis<\/jats:named-content>clearance has not been determined. Therefore, RAG2<jats:sup>\u2212\/\u2212<\/jats:sup>mice lacking either the interferon gamma (IFN-\u03b3) receptor (IFN-\u03b3R) or interleukin 4 receptor alpha (IL-4R\u03b1) were infected with<jats:named-content content-type=\"genus-species\">Pneumocystis<\/jats:named-content>. 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<jats:sup>\u2212\/\u2212<\/jats:sup>mice developed severe disease but effectively cleared<jats:named-content content-type=\"genus-species\">Pneumocystis<\/jats:named-content>and resolved IRIS. Neither RAG\/IFN-\u03b3R<jats:sup>\u2212\/\u2212<\/jats:sup>nor RAG\/IL-4R\u03b1<jats:sup>\u2212\/\u2212<\/jats:sup>mice displayed impaired<jats:named-content content-type=\"genus-species\">Pneumocystis<\/jats:named-content>clearance. However, RAG\/IFN-\u03b3R<jats:sup>\u2212\/\u2212<\/jats:sup>mice developed a dysregulated immune response, with exacerbated IRIS and greater pulmonary function deficits than those in RAG2 and RAG\/IL-4R\u03b1<jats:sup>\u2212\/\u2212<\/jats:sup>mice. RAG\/IFN-\u03b3R<jats:sup>\u2212\/\u2212<\/jats:sup>mice had elevated numbers of lung CD4<jats:sup>+<\/jats:sup>T cells, neutrophils, eosinophils, and NK cells but severely depressed numbers of lung CD8<jats:sup>+<\/jats:sup>T suppressor cells. Impaired lung CD8<jats:sup>+<\/jats:sup>T cell responses in RAG\/IFN-\u03b3R<jats:sup>\u2212\/\u2212<\/jats:sup>mice were associated with elevated lung IFN-\u03b3 levels, and neutralization of IFN-\u03b3 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<jats:named-content content-type=\"genus-species\">Pneumocystis<\/jats:named-content>clearance. However, a cell type-specific IFN-\u03b3\/IFN-\u03b3R-dependent mechanism regulates CD8<jats:sup>+<\/jats:sup>T suppressor cell recruitment, limits immunopathogenesis, preserves lung function, and enhances the resolution of PcP-related IRIS.<\/jats:p>","DOI":"10.1128\/iai.00763-15","type":"journal-article","created":{"date-parts":[[2015,9,15]],"date-time":"2015-09-15T02:08:54Z","timestamp":1442282934000},"page":"4594-4603","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":17,"title":["Neither Classical nor Alternative Macrophage Activation Is Required for Pneumocystis Clearance during Immune Reconstitution Inflammatory Syndrome"],"prefix":"10.1128","volume":"83","author":[{"given":"Zhuo-Qian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Hoy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achsah","family":"Keegan","sequence":"additional","affiliation":[{"name":"Center for Vascular and Inflammatory Diseases, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"Bhagwat","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Gigliotti","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA"},{"name":"Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry W.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA"},{"name":"Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/319340"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb\/5.2.186"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-8-118"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-006-9250-x"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1159\/000334113"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2011.05.008"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/139.6.1336"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0954-6111(95)90089-6"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-199105000-00008"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/140.5.1204"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.2217\/17520363.2.4.349"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1468-1293.2002.00115.x"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-111-3-223"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115910"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1086\/315487"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.050724"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2004.09.015"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001058"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.17.7681"},{"key":"e_1_3_2_21_2","doi-asserted-by":"crossref","first-page":"849","DOI":"10.4049\/jimmunol.141.3.849","article-title":"Simultaneous production of IL-2, IL-4, and IFN-gamma by activated human CD4+ and CD8+ T cell clones","volume":"141","author":"Paliard X","year":"1988","unstructured":"Paliard X, de Waal Malefijt R, Yssel H, Blanchard D, Chretien I, Abrams J, de Vries J, Spits H. 1988. 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