{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T03:34:06Z","timestamp":1777779246080,"version":"3.51.4"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2016,2,1]],"date-time":"2016-02-01T00:00:00Z","timestamp":1454284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Patients with acquired deficiency in GM-CSF are susceptible to infections with Cryptococcus neoformans and other opportunistic fungi. We previously showed that GM-CSF protects against progressive fungal disease using a murine model of cryptococcal lung infection. To better understand the cellular and molecular mechanisms through which GM-CSF enhances antifungal host defenses, we investigated temporal and spatial relationships between myeloid and lymphoid immune responses in wild-type C57BL\/6 mice capable of producing GM-CSF and GM-CSF\u2013deficient mice infected with a moderately virulent encapsulated strain of C. neoformans (strain 52D). Our data demonstrate that GM-CSF deficiency led to a reduction in: 1) total lung leukocyte recruitment; 2) Th2 and Th17 responses; 3) total numbers of CD11b+ dendritic cells (DC) and CD11b\u2212 and CD11b+ macrophages (M\u03d5); 4) DC and M\u03d5 activation; and 5) localization of DC and M\u03d5 to the microanatomic sites of alveolar infection. In contrast, GM-CSF deficiency resulted in increased accumulation of DC and M\u03d5 precursors, namely Ly-6Chigh monocytes, in the blood and lungs of infected mice. Collectively, these results show that GM-CSF promotes the local differentiation, accumulation, activation, and alveolar localization of lung DC and M\u03d5 in mice with cryptococcal lung infection. These findings identify GM-CSF as central to the protective immune response that prevents progressive fungal disease and thus shed new light on the increased susceptibility to these infections observed in patients with acquired GM-CSF deficiency.<\/jats:p>","DOI":"10.4049\/jimmunol.1501512","type":"journal-article","created":{"date-parts":[[2016,1,12]],"date-time":"2016-01-12T03:39:02Z","timestamp":1452569942000},"page":"1810-1821","source":"Crossref","is-referenced-by-count":44,"title":["Local GM-CSF\u2013Dependent Differentiation and Activation of Pulmonary Dendritic Cells and Macrophages Protect against Progressive Cryptococcal Lung Infection in Mice"],"prefix":"10.1093","volume":"196","author":[{"given":"Gwo-Hsiao","family":"Chen","sequence":"first","affiliation":[{"name":"Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seagal","family":"Teitz-Tennenbaum","sequence":"additional","affiliation":[{"name":"Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lori M","family":"Neal","sequence":"additional","affiliation":[{"name":"Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin J","family":"Murdock","sequence":"additional","affiliation":[{"name":"Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoni N","family":"Malachowski","sequence":"additional","affiliation":[{"name":"Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony J","family":"Dils","sequence":"additional","affiliation":[{"name":"Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal A","family":"Olszewski","sequence":"additional","affiliation":[{"name":"Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"},{"name":"Graduate Program in Immunology, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John J","family":"Osterholzer","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"},{"name":"Graduate Program in Immunology, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"},{"name":"Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System , Ann Arbor, MI 48105"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2016,2,15]]},"reference":[{"key":"2025030702130559700_r1","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1513\/pats.200907-063AL","article-title":"Cryptococcus","volume":"7","author":"Li","year":"2010","journal-title":"Proc. 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Immunol."},{"key":"2025030702130559700_r9","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1182\/blood-2008-12-164004","article-title":"The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease","volume":"114","author":"Hercus","year":"2009","journal-title":"Blood"},{"key":"2025030702130559700_r10","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1084\/jem.190.6.875","article-title":"Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte\/macrophage colony-stimulating factor","volume":"190","author":"Kitamura","year":"1999","journal-title":"J. Exp. 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