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Using a mouse model of cryptococcal infection, we investigated the mechanism by which disruption of early TNF-\u03b1 signaling results in the development of nonprotective immunity against<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>. We found that transient depletion of TNF-\u03b1 inhibited pulmonary fungal clearance and enhanced extrapulmonary dissemination of<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>during the adaptive phase of the immune response. Higher fungal burdens in TNF-\u03b1-depleted mice were accompanied by markedly impaired Th1 and Th17 responses in the infected lungs. Furthermore, early TNF-\u03b1 depletion also resulted in disrupted transcriptional initiation of the Th17 polarization program and subsequent upregulation of Th1 genes in CD4<jats:sup>+<\/jats:sup>T cells in the lung-associated lymph nodes (LALN) of<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>-infected mice. These defects in LALN T cell responses were preceded by a dramatic shift from a classical toward an alternative activation of dendritic cells (DC) in the LALN of TNF-\u03b1-depleted mice. Taken together, our results indicate that early TNF-\u03b1 signaling is required for optimal DC activation, and the initial Th17 response followed by Th1 transcriptional prepolarization of T cells in the LALN, which further drives the development of protective immunity against cryptococcal infection in the lungs. Thus, administration of anti-TNF-\u03b1 may introduce a particularly greater risk for newly acquired fungal infections that require generation of protective Th1\/Th17 responses for their containment and clearance.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Increased susceptibility to invasive fungal infections in patients on anti-TNF-\u03b1 therapies underlines the need for understanding the cellular effects of TNF-\u03b1 signaling in promoting protective immunity to fungal pathogens. Here, we demonstrate that early TNF-\u03b1 signaling is required for classical activation and accumulation of DC in LALN of<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>-infected mice. Subsequent transcriptional initiation of Th17 followed by Th1 programming in LALN results in pulmonary accumulation of gamma interferon- and interleukin-17A-producing T cells and effective fungal clearance. All of these crucial steps are severely impaired in mice that undergo anti-TNF-\u03b1 treatment, consistent with their inability to clear<jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>. This study identified critical interactions between cells of the innate immune system (DC), the emerging T cell responses, and cytokine networks with a central role for TNF-\u03b1 which orchestrate the development of the immune protection against cryptococcal infection. This information will be important in aiding development and understanding the potential side effects of immunotherapies.<\/jats:p>","DOI":"10.1128\/mbio.00510-16","type":"journal-article","created":{"date-parts":[[2016,7,13]],"date-time":"2016-07-13T01:24:17Z","timestamp":1468373057000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":28,"title":["Disruption of Early Tumor Necrosis Factor Alpha Signaling Prevents Classical Activation of Dendritic Cells in Lung-Associated Lymph Nodes and Development of Protective Immunity against Cryptococcal Infection"],"prefix":"10.1128","volume":"7","author":[{"given":"Jintao","family":"Xu","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA"},{"name":"Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs 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