title: CD103+ Conventional Dendritic Cells Are Critical for TLR7/9-Dependent Host Defense against Histoplasma capsulatum, an Endemic Fungal Pathogen of Humans.
abstract: Innate immune cells shape the host response to microbial pathogens. Here we elucidate critical differences in the molecular response of macrophages vs. dendritic cells (DCs) to Histoplasma capsulatum, an intracellular fungal pathogen of humans. It has long been known that macrophages are permissive for Histoplasma growth and succumb to infection, whereas DCs restrict fungal growth and survive infection. We used murine macrophages and DCs to identify host pathways that influence fungal proliferation and host-cell viability. Transcriptional profiling experiments revealed that DCs produced a strong Type I interferon (IFN-I) response to infection with Histoplasma yeasts. Toll-like receptors 7 and 9 (TLR7/9), which recognize nucleic acids, were required for IFN-I production and restriction of fungal growth in DCs, but mutation of TLR7/9 had no effect on the outcome of macrophage infection. Moreover, TLR7/9 were essential for the ability of infected DCs to elicit production of the critical cytokine IFNγ from primed CD4+ T cells in vitro, indicating the role of this pathway in T cell activation. In a mouse model of infection, TLR7/9 were required for optimal production of IFN-I and IFNγ, host survival, and restriction of cerebral fungal burden. These data demonstrate the critical role of this pathway in eliciting an appropriate adaptive immune response in the host. Finally, although other fungal pathogens have been shown to elicit IFN-I in mouse models, the specific host cell responsible for producing IFN-I has not been elucidated. We found that CD103+ conventional DCs were the major producer of IFN-I in the lungs of wild-type mice infected with Histoplasma. Mice deficient in this DC subtype displayed reduced IFN-I production in vivo. These data reveal a previously unknown role for CD103+ conventional DCs and uncover the pivotal function of these cells in modulating the host immune response to endemic fungi.
authors.affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Nancy
authors.initials: N
authors.lastname: Van Prooyen
authors.affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: C Allen
authors.initials: CA
authors.lastname: Henderson
authors.affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Davina
authors.initials: D
authors.lastname: Hocking Murray
authors.affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America.|Howard Hughes Medical Institute, San Francisco, California, United States of America.
authors.forename: Anita
authors.initials: A
authors.lastname: Sil
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000469:parasitology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006658:Histoplasma / Q000276:immunology; D006660:Histoplasmosis / Q000276:immunology*; D006801:Humans; D039001:Integrin alpha Chains / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D051199:Toll-Like Receptor 7 / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D039001:Integrin alpha Chains; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C091367:alpha E integrins