{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T08:52:59Z","timestamp":1781427179756,"version":"3.54.1"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2012,4,1]],"date-time":"2012-04-01T00:00:00Z","timestamp":1333238400000},"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":[[2012,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We investigated mechanisms by which TLR9 signaling promoted the development of the protective response to Cryptococcus neoformans in mice with cryptococcal pneumonia. The afferent (week 1) and efferent (week 3) phase immune parameters were analyzed in the infected wild-type (TLR9+\/+) and TLR-deficient (TLR9\u2212\/\u2212) mice. TLR9 deletion diminished 1) accumulation and activation of CD11b+ dendritic cells (DCs), 2) the induction of IFN-\u03b3 and CCR2 chemokines CCL7, CCL12, but not CCL2, at week 1, and 3) pulmonary accumulation and activation of the major effector cells CD4+ and CD8+ T cells, CD11b+ lung DCs, and exudate macrophages at week 3. The significance of CCL7 induction downstream of TLR9 signaling was investigated by determining whether CCL7 reconstitution would improve immunological parameters in C. neoformans-infected TLR9\u2212\/\u2212 mice. Early reconstitution with CCL7 1) improved accumulation and activation of CD11b+ DCs at week 1, 2) restored early IFN-\u03b3 production in the lungs, and 3) restored the accumulation of major effector cell subsets. CCL7 administration abolished the difference in lung fungal burdens between TLR9+\/+ and TLR9\u2212\/\u2212 mice at week 3; however, significant reduction of fungal burdens between PBS- and CCL7-treated mice has not been observed, suggesting that additional mechanism(s) apart from early CCL7 induction contribute to optimal fungal clearance in TLR9+\/+ mice. Collectively, we show that TLR9 signaling during the afferent phase contributes to the development of protective immunity by promoting the early induction of CCL7 and IFN-\u03b3 and the subsequent early recruitment and activation of DCs and additional effector cells in mice with cryptococcal pneumonia.<\/jats:p>","DOI":"10.4049\/jimmunol.1103053","type":"journal-article","created":{"date-parts":[[2012,3,15]],"date-time":"2012-03-15T07:33:41Z","timestamp":1331796821000},"page":"3940-3948","source":"Crossref","is-referenced-by-count":45,"title":["Early Induction of CCL7 Downstream of TLR9 Signaling Promotes the Development of Robust Immunity to Cryptococcal Infection"],"prefix":"10.1093","volume":"188","author":[{"given":"Yafeng","family":"Qiu","sequence":"first","affiliation":[{"name":"Department of Research Service, Veterans Administration Ann Arbor Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Zeltzer","sequence":"additional","affiliation":[{"name":"Department of Research Service, Veterans Administration Ann Arbor Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Research Service, Veterans Administration Ann Arbor Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwo-Hsiao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Research Service, Veterans Administration Ann Arbor Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Dayrit","sequence":"additional","affiliation":[{"name":"Department of Research Service, Veterans Administration Ann Arbor Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J","family":"Murdock","sequence":"additional","affiliation":[{"name":"Department of Research Service, Veterans Administration Ann Arbor Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urvashi","family":"Bhan","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galen B","family":"Toews","sequence":"additional","affiliation":[{"name":"Department of Research Service, Veterans Administration Ann Arbor Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J","family":"Osterholzer","sequence":"additional","affiliation":[{"name":"Department of Research Service, Veterans Administration Ann Arbor Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore J","family":"Standiford","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal A","family":"Olszewski","sequence":"additional","affiliation":[{"name":"Department of Research Service, Veterans Administration Ann Arbor Health System , Ann Arbor, MI 48105"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,4,15]]},"reference":[{"key":"2025032410012993400_r1","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1056\/NEJM198909213211205","article-title":"Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome","volume":"321","author":"Chuck","year":"1989","journal-title":"N. Engl. J. Med."},{"key":"2025032410012993400_r2","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1086\/322597","article-title":"Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy","volume":"33","author":"Pappas","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"2025032410012993400_r3","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/jlb.55.1.35","article-title":"The role of CD4+ and CD8+ T cells in the protective inflammatory response to a pulmonary cryptococcal infection","volume":"55","author":"Huffnagle","year":"1994","journal-title":"J. Leukoc. Biol."},{"key":"2025032410012993400_r4","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1084\/jem.173.4.793","article-title":"Immunity to a pulmonary Cryptococcus neoformans infection requires both CD4+ and CD8+ T cells","volume":"173","author":"Huffnagle","year":"1991","journal-title":"J. Exp. Med."},{"key":"2025032410012993400_r5","first-page":"765","article-title":"Depletion of murine CD8+ T cells in vivo decreases pulmonary clearance of a moderately virulent strain of Cryptococcus neoformans","volume":"121","author":"Mody","year":"1993","journal-title":"J. Lab. Clin. Med."},{"key":"2025032410012993400_r6","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1128\/iai.59.4.1423-1433.1991","article-title":"T cell-mediated immunity in the lung: a Cryptococcus neoformans pulmonary infection model using SCID and athymic nude mice","volume":"59","author":"Huffnagle","year":"1991","journal-title":"Infect. Immun."},{"key":"2025032410012993400_r7","doi-asserted-by":"crossref","first-page":"6346","DOI":"10.4049\/jimmunol.174.10.6346","article-title":"Role of IFN-gamma in regulating T2 immunity and the development of alternatively activated macrophages during allergic bronchopulmonary mycosis","volume":"174","author":"Arora","year":"2005","journal-title":"J. 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