The role of dendritic cells in vaccine-mediated anti-fungal immunity

• Main Author: Ersland, Karen Keke
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2010
• Subjects: Immunology; Microbiology
• ISBN: 9781124548111; 1124548114

The generation of vaccine-mediated immunity requires an understanding of the elements critical to a protective immune response. The live-attenuated vaccine against the dimorphic fungus Blastomyces dermatitidis provides a model for the study of the protective anti-fungal response. Subcutaneous, but not intra-tracheal, vaccination with attenuated B. dermatitidis yeast elicits a protective CD4+ T-cell response. The antigen presenting cells (APCs) that prime these protective T cells remain unidentified. In recent years, APCs, particularly dendritic cells (DCs) have been implicated in the generation of vaccine-induced immunity due to their versatility in stimulating the immune system. Elucidating the identity of the DCs that activate T-cells in response to B. dermatitidis will clarify a key mechanism of anti-fungal vaccine-mediated immunity. Because the B. dermatitidis vaccine is effective when administered subcutaenously, we characterized the DCs in the skin-draining lymph node. Our analysis revealed B. dermatitidis yeast within three DC populations: monocyte-derived/inflammatory DCs, interstitial/dermal DCs, and conventional lymph node resident DCs. Although inflammatory DCs are the first and most abundant cells to associate with vaccine yeast, they fail to display antigen or prime naive antigen-specific CD4+ T cells. The ability to prime naïve T cells resides primarily with dermal DCs, which migrate to the lymph node after acquiring antigen at the site of vaccination, and lymph node resident DCs, which acquire antigen from the migratory DC subsets. Although the respiratory mucosa is the natural route of infection, intra-tracheal delivery of the B. dermatitidis vaccine fails to induce a protective T cell response. In contrast, the dimorphic fungus Histoplasma capsulatum induces a protective response, together with an influx of Ly6Chigh inflammatory monocyte-derived DCs into the lung. B. dermatitidis yeast blocks the recruitment and maturation of these inflammatory DCs, either when given alone or during mixed inoculation with H. capsulatum. Adoptive transfer of Ly6Chigh monocyte-derived DCs into the lungs of B. dermatitidis vaccinated animals restored T cell priming, establishing the key role of these DCs for vaccine priming at the respiratory mucosa. Thus, a complex network of DCs is essential for T cell priming during the generation of vaccine-mediated immunity to the dimorphic fungus B. dermatitidis.