{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:39:41Z","timestamp":1791275981090,"version":"4.1.0"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2009,12,1]],"date-time":"2009-12-01T00:00:00Z","timestamp":1259625600000},"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":[[2009,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pulmonary clearance of the encapsulated yeast Cryptococcus neoformans is associated with the CCR2-mediated accumulation of lung dendritic cells (DC) and the development of a T1 adaptive immune response. The objective of this study was to identify the circulating DC precursor(s) responsible for this large increase in lung DC numbers. An established murine model was used to evaluate putative DC precursors in the blood, bone marrow, and lungs of CCR2+\/+ mice and CCR2\u2212\/\u2212 mice throughout a time course following infection with C. neoformans. Results demonstrate that numbers of Ly-6Chigh monocytes increased in parallel in the peripheral blood and lungs of CCR+\/+ mice, whereas CD11c+ MHC class II+ pre-DC were 10-fold less prevalent in the peripheral blood and did not differ between the two strains. Accumulation of Ly-6Chigh monocytes correlated with a substantial increase in the numbers of CD11b+ DC in the lungs of infected CCR2+\/+ mice. Comparative phenotypic analysis of lung cells recovered in vivo suggests that Ly-6Chigh monocytes differentiate into CD11b+ DC in the lung; differentiation is associated with up-regulation of costimulatory molecules and decreased Ly-6C expression. Furthermore, in vitro experiments confirmed that Ly-6Chigh monocytes differentiate into CD11b+ DC. Accumulation of Ly-6Chigh monocytes and CD11b+ DC was not attributable to their proliferation in situ. We conclude that the CCR2-mediated accumulation of CD11b+ DC in the lungs of Cryptococcus-infected mice is primarily attributable to the continuous recruitment and differentiation of Ly-6Chigh monocytes.<\/jats:p>","DOI":"10.4049\/jimmunol.0902823","type":"journal-article","created":{"date-parts":[[2009,11,23]],"date-time":"2009-11-23T22:59:20Z","timestamp":1259017160000},"page":"8044-8053","source":"Crossref","is-referenced-by-count":110,"title":["Accumulation of CD11b+ Lung Dendritic Cells in Response to Fungal Infection Results from the CCR2-Mediated Recruitment and Differentiation of Ly-6Chigh Monocytes"],"prefix":"10.1093","volume":"183","author":[{"given":"John J","family":"Osterholzer","sequence":"first","affiliation":[{"name":"Pulmonary Section, Medical Service"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwo-Hsiao","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal A","family":"Olszewski","sequence":"additional","affiliation":[{"name":"Research Service, Ann Arbor Veterans Affairs 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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L","family":"Curtis","sequence":"additional","affiliation":[{"name":"Pulmonary Section, Medical Service"},{"name":"Graduate Program in Immunology"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary B","family":"Huffnagle","sequence":"additional","affiliation":[{"name":"Graduate Program in Immunology"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galen B","family":"Toews","sequence":"additional","affiliation":[{"name":"Pulmonary Section, Medical Service"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,15]]},"reference":[{"key":"2026012811241792500_R1","first-page":"442","article-title":"Division of labor between dendritic cell subsets of the lung.","volume-title":"Mucosal Immunol.","year":"2008"},{"key":"2026012811241792500_R2","first-page":"17","article-title":"Dendritic cells: translating innate to adaptive immunity.","volume-title":"Curr. Top. Microbiol. Immunol.","year":"2006"},{"key":"2026012811241792500_R3","first-page":"530","article-title":"Pulmonary dendritic cells.","volume-title":"Am. J. Respir. Crit. Care Med.","year":"2005"},{"key":"2026012811241792500_R4","first-page":"932","article-title":"Cryptococcal urease promotes the accumulation of immature dendritic cells and a non-protective T2 immune response within the lung.","volume-title":"Am. J. Pathol.","year":"2009"},{"key":"2026012811241792500_R5","first-page":"3749","article-title":"Role of dendritic cells and alveolar macrophages in regulating early host defense against pulmonary infection with Cryptococcus neoformans.","volume-title":"Infect. Immun.","year":"2009"},{"key":"2026012811241792500_R6","first-page":"6349","article-title":"Tuberculosis triggers a tissue-dependent program of differentiation and acquisition of effector functions by circulating monocytes.","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012811241792500_R7","first-page":"610","article-title":"CCR2 mediates conventional dendritic cell recruitment and the formation of bronchovascular mononuclear cell infiltrates in the lungs of mice infected with Cryptococcus neoformans.","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012811241792500_R8","first-page":"2562","article-title":"CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality.","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012811241792500_R9","first-page":"5828","article-title":"Lung-specific overexpression of CC chemokine ligand (CCL) 2 enhances the host defense to Streptococcus pneumoniae infection in mice: role of the CCL2-CCR2 axis.","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012811241792500_R10","first-page":"5305","article-title":"Chemokine receptor CCR2 but not CCR5 or CCR6 mediates the increase in pulmonary dendritic cells during allergic airway inflammation.","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012811241792500_R11","first-page":"3937","article-title":"TLR9 is required for protective innate immunity in Gram-\u2212ative bacterial pneumonia: role of dendritic cells.","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012811241792500_R12","first-page":"3817","article-title":"In vivo role of dendritic cells in a murine model of pulmonary cryptococcosis.","volume-title":"Infect. Immun.","year":"2006"},{"key":"2026012811241792500_R13","first-page":"874","article-title":"CCR2 and CCR6, but not endothelial selectins, mediate the accumulation of immature dendritic cells within the lungs of mice in response to particulate antigen.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012811241792500_R14","first-page":"7647","article-title":"CCR2-dependent trafficking of F4\/80dim macrophages and CD11cdim\/intermediate dendritic cells is crucial for T cell recruitment to lungs infected with Mycobacterium tuberculosis.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012811241792500_R15","first-page":"3273","article-title":"Monocytes are potent facilitators of alveolar neutrophil emigration during lung inflammation: role of the CCL2-CCR2 axis.","volume-title":"J. Immunol.","year":"2003"},{"key":"2026012811241792500_R16","first-page":"234","article-title":"Innate immune control of pulmonary dendritic cell trafficking.","volume-title":"Proc. Am. Thorac. Soc.","year":"2007"},{"key":"2026012811241792500_R17","first-page":"692","article-title":"Lung dendritic cells and host immunity to infection.","volume-title":"Eur. Respir. J.","year":"2001"},{"key":"2026012811241792500_R18","first-page":"1621","article-title":"Clearance of influenza virus from the lung depends on migratory langerin+CD11b\u2212 but not plasmacytoid dendritic cells.","volume-title":"J. Exp. Med.","year":"2008"},{"key":"2026012811241792500_R19","first-page":"981","article-title":"In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma.","volume-title":"J. Exp. Med.","year":"2005"},{"key":"2026012811241792500_R20","first-page":"5306","article-title":"TNF\/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2009"},{"key":"2026012811241792500_R21","first-page":"2395","article-title":"Pulmonary cryptococcosis after initiation of anti-tumor necrosis factor-\u03b1 therapy.","volume-title":"Chest","year":"2003"},{"key":"2026012811241792500_R22","first-page":"533","article-title":"Cryptococcosis in the acquired immunodeficiency syndrome.","volume-title":"Ann. Intern. Med.","year":"1985"},{"key":"2026012811241792500_R23","first-page":"205","article-title":"Cryptococcosis: clinical and biological aspects.","volume-title":"Med. Mycol.","year":"2000"},{"key":"2026012811241792500_R24","first-page":"935","article-title":"Cryptococcus neoformans infections at Vancouver Hospital and Health Sciences Centre (1997\u20132002): epidemiology, microbiology and histopathology.","volume-title":"J. Med. Microbiol.","year":"2004"},{"key":"2026012811241792500_R25","first-page":"187","article-title":"[Disseminated pulmonary infection due to Cryptococcus neoformans in a non immunocompromised patient].","volume-title":"Ann. Pathol.","year":"2004"},{"key":"2026012811241792500_R26","first-page":"168","article-title":"Cryptococcal meningitis in two apparently immunocompetent Maltese patients.","volume-title":"Mycoses","year":"2004"},{"key":"2026012811241792500_R27","first-page":"68","article-title":"Effects of tumor necrosis factor \u03b1 on dendritic cell accumulation in lymph nodes draining the immunization site and the impact on the anticryptococcal cell-mediated immune response.","volume-title":"Infect. Immun.","year":"2003"},{"key":"2026012811241792500_R28","first-page":"1788","article-title":"The \u03b3 interferon receptor is required for the protective pulmonary inflammatory response to Cryptococcus neoformans.","volume-title":"Infect. Immun.","year":"2005"},{"key":"2026012811241792500_R29","first-page":"39","article-title":"Transient neutralization of tumor necrosis factor \u03b1 can produce a chronic fungal infection in an immunocompetent host: potential role of immature dendritic cells.","volume-title":"Infect. Immun.","year":"2005"},{"key":"2026012811241792500_R30","first-page":"387","article-title":"Cells and cytokines in pulmonary cryptococcosis.","volume-title":"Res. Immunol.","year":"1998"},{"key":"2026012811241792500_R31","first-page":"35","article-title":"The role of CD4+ and CD8+ T cells in the protective inflammatory response to a pulmonary cryptococcal infection.","volume-title":"J. Leukocyte. Biol.","year":"1994"},{"key":"2026012811241792500_R32","first-page":"4529","article-title":"Afferent phase production of TNF-\u03b1 is required for the development of protective T cell immunity to Cryptococcus neoformans.","volume-title":"J. Immunol.","year":"1996"},{"key":"2026012811241792500_R33","first-page":"1423","article-title":"T cell-mediated immunity in the lung: a Cryptococcus neoformans pulmonary infection model using SCID and athymic nude mice.","volume-title":"Infect. Immun.","year":"1991"},{"key":"2026012811241792500_R34","first-page":"208","article-title":"IL-12 protects mice against pulmonary and disseminated infection caused by Cryptococcus neoformans.","volume-title":"Clin. Exp. Immunol.","year":"1996"},{"key":"2026012811241792500_R35","first-page":"2021","article-title":"CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection.","volume-title":"J. Immunol.","year":"2000"},{"key":"2026012811241792500_R36","first-page":"311","article-title":"Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2.","volume-title":"Nat. Immunol.","year":"2006"},{"key":"2026012811241792500_R37","first-page":"669","article-title":"Blood monocytes: development, heterogeneity, and relationship with dendritic cells.","volume-title":"Annu. Rev. Immunol.","year":"2009"},{"key":"2026012811241792500_R38","first-page":"421","article-title":"Monocyte-mediated defense against microbial pathogens.","volume-title":"Annu. Rev. Immunol.","year":"2008"},{"key":"2026012811241792500_R39","first-page":"12053","article-title":"Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1997"},{"key":"2026012811241792500_R40","first-page":"520","article-title":"Adhesion receptor phenotypes of murine lung CD4+ T cells during a pulmonary immune response to sheep erythrocytes.","volume-title":"Am. J. Respir. Cell Mol. Biol.","year":"1995"},{"key":"2026012811241792500_R41","first-page":"138","article-title":"Characterization of murine dendritic cells derived from adherent blood mononuclear cells in vitro.","volume-title":"Scand. J. Immunol.","year":"2000"},{"key":"2026012811241792500_R42","first-page":"626","article-title":"A novel method based on click chemistry, which overcomes limitations of cell cycle analysis by classical determination of BrdU incorporation, allowing multiplex antibody staining.","volume-title":"Cytometry A","year":"2008"},{"key":"2026012811241792500_R43","first-page":"2415","article-title":"A chemical method for fast and sensitive detection of DNA synthesis in vivo.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2008"},{"key":"2026012811241792500_R44","volume-title":"Biostastical Analysis","year":"1974"},{"key":"2026012811241792500_R45","first-page":"835","article-title":"The concerted action of GM-CSF and Flt3-ligand on in vivo dendritic cell homeostasis.","volume-title":"Blood","year":"2009"},{"key":"2026012811241792500_R46","first-page":"1217","article-title":"Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo.","volume-title":"Nat. Immunol.","year":"2007"},{"key":"2026012811241792500_R47","first-page":"1207","article-title":"Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow.","volume-title":"Nat. Immunol.","year":"2007"},{"key":"2026012811241792500_R48","first-page":"4659","article-title":"Differential roles of CC chemokine ligand 2\/monocyte chemotactic protein-1 and CCR2 in the development of T1 immunity.","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012811241792500_R49","first-page":"111","article-title":"A rapid flow cytometric method for determining the cellular composition of bronchoalveolar lavage fluid cells in mouse models of asthma.","volume-title":"J. Immunol. Methods","year":"2004"},{"key":"2026012811241792500_R50","first-page":"3663","article-title":"Allergen-induced accumulation of airway dendritic cells is supported by an increase in CD31hiLy-6Cneg bone marrow precursors in a mouse model of asthma.","volume-title":"Blood","year":"2002"},{"key":"2026012811241792500_R51","first-page":"2161","article-title":"A major lung CD103 (\u03b1E)-\u03b27 integrin-positive epithelial dendritic cell population expressing Langerin and tight junction proteins.","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012811241792500_R52","first-page":"4410","article-title":"Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012811241792500_R53","first-page":"6915","article-title":"Differentiation to the CCR2+ inflammatory phenotype in vivo is a constitutive, time-limited property of blood monocytes and is independent of local inflammatory mediators.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012811241792500_R54","first-page":"7.34.1","article-title":"Cell proliferation method: click chemistry based on BrdU coupling for multiplex antibody staining.","volume-title":"Curr. Protoc. Cytom.","year":"2008"},{"key":"2026012811241792500_R55","first-page":"L587","article-title":"Polymorphonuclear leukocyte transit times in bone marrow during streptococcal pneumonia.","volume-title":"Am. J. Physiol.","year":"1996"},{"key":"2026012811241792500_R56","first-page":"6846","article-title":"Additive roles for MCP-1 and MCP-3 in CCR2-mediated recruitment of inflammatory monocytes during Listeria monocytogenes infection.","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012811241792500_R57","first-page":"902","article-title":"Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites.","volume-title":"J. Clin. Invest.","year":"2007"},{"key":"2026012811241792500_R58","first-page":"2810","article-title":"Regulation of inflammatory monocyte\/macrophage recruitment from the bone marrow during murine cytomegalovirus infection: role for type I interferons in localized induction of CCR2 ligands.","volume-title":"J. Immunol.","year":"2009"},{"key":"2026012811241792500_R59","first-page":"3019","article-title":"Blood monocyte subsets differentially give rise to CD103+ and CD103\u2212 pulmonary dendritic cell populations.","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012811241792500_R60","first-page":"2000","article-title":"Distinct differentiation potential of blood monocyte subsets in the lung.","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012811241792500_R61","first-page":"6511","article-title":"Host-pathogen interactions: basic concepts of microbial commensalism, colonization, infection, and disease.","volume-title":"Infect. Immun.","year":"2000"},{"key":"2026012811241792500_R62","first-page":"166","article-title":"Extracellular phospholipase activity is a virulence factor for Cryptococcus neoformans.","volume-title":"Mol. Microbiol.","year":"2001"},{"key":"2026012811241792500_R63","first-page":"129","article-title":"Capsule size of Cryptococcus neoformans: control and relationship to virulence.","volume-title":"Infect. Immun.","year":"1977"},{"key":"2026012811241792500_R64","first-page":"4322","article-title":"Phenotypic switching in Cryptococcus neoformans contributes to virulence by changing the immunological host response.","volume-title":"Infect. Immun.","year":"2008"},{"key":"2026012811241792500_R65","first-page":"2054","article-title":"Attenuation of allergen-induced responses in CCR6\u2212\/\u2212 mice is dependent upon altered pulmonary T lymphocyte activation.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012811241792500_R66","first-page":"1165","article-title":"The role of CC chemokine receptor 6 in host defense in a model of invasive pulmonary aspergillosis.","volume-title":"Am. J. Respir. Crit. Care Med.","year":"2007"},{"key":"2026012811241792500_R67","first-page":"7958","article-title":"Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2001"},{"key":"2026012811241792500_R68","first-page":"1951","article-title":"Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus.","volume-title":"Am. J. Pathol.","year":"2000"},{"key":"2026012811241792500_R69","first-page":"1964","article-title":"The CCL7-CCL2-CCR2 axis regulates IL-4 production in lungs and fungal immunity.","volume-title":"J. Immunol.","year":"2009"},{"key":"2026012811241792500_R70","first-page":"2339","article-title":"Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice.","volume-title":"J. Exp. Med.","year":"2009"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/12\/8044\/62692840\/0148.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/12\/8044\/62692840\/0148.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T16:25:49Z","timestamp":1769617549000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/183\/12\/8044\/8053279"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,12]]},"references-count":70,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2009,12,15]]},"published-print":{"date-parts":[[2009,12,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0902823","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,12]]},"published":{"date-parts":[[2009,12]]}}}