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.
abstract: Anti-tumor necrosis factor alpha (anti-TNF-α) therapies have been increasingly used to treat inflammatory diseases and are associated with increased risk of invasive fungal infections, including Cryptococcus neoformans infection. Using a mouse model of cryptococcal infection, we investigated the mechanism by which disruption of early TNF-α signaling results in the development of nonprotective immunity against C. neoformans We found that transient depletion of TNF-α inhibited pulmonary fungal clearance and enhanced extrapulmonary dissemination of C. neoformans during the adaptive phase of the immune response. Higher fungal burdens in TNF-α-depleted mice were accompanied by markedly impaired Th1 and Th17 responses in the infected lungs. Furthermore, early TNF-α depletion also resulted in disrupted transcriptional initiation of the Th17 polarization program and subsequent upregulation of Th1 genes in CD4(+) T cells in the lung-associated lymph nodes (LALN) of C. neoformans-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-α-depleted mice. Taken together, our results indicate that early TNF-α 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-α may introduce a particularly greater risk for newly acquired fungal infections that require generation of protective Th1/Th17 responses for their containment and clearance.
  
  
  
  Increased susceptibility to invasive fungal infections in patients on anti-TNF-α therapies underlines the need for understanding the cellular effects of TNF-α signaling in promoting protective immunity to fungal pathogens. Here, we demonstrate that early TNF-α signaling is required for classical activation and accumulation of DC in LALN of C. neoformans-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-α treatment, consistent with their inability to clear C. neoformans 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-α 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.
authors.forename: Jintao
authors.initials: J
authors.lastname: Xu
authors.affiliation: Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Eastman
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Flaczyk
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.
authors.forename: Lori M
authors.initials: LM
authors.lastname: Neal
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.
authors.forename: Guolei
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Carolan
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.
authors.forename: Antoni N
authors.initials: AN
authors.lastname: Malachowski
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.
authors.forename: Valerie R
authors.initials: VR
authors.lastname: Stolberg
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Yosri
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Chensue
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Curtis
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Osterholzer
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, Michigan, USA Pulmonary Section, Medical Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, Michigan, USA olszewsm@umich.edu.
authors.forename: Michal A
authors.initials: MA
authors.lastname: Olszewski
mesh_terms: D000818:Animals; D058491:Bacterial Load; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003453:Cryptococcosis / Q000276:immunology* / Q000517:prevention & control*; D003455:Cryptococcus neoformans / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008171:Lung Diseases / Q000276:immunology* / Q000517:prevention & control*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D014409:Tumor Necrosis Factor-alpha