Dendritic cells cross-present exogenous fungal antigens to stimulate a protective CD8 T cell response in infection by Histoplasma capsulatum

The contribution of CD8 T cells in host defense against histoplasmosis is minor in the CD4 T cell-intact mouse, as it has been shown that depleting CD8 T cells only marginally affects fungal clearance. However, it remains to be determined whether the CD8 T cells are protective in a host lacking functional CD4 T cells. In this study, MHC class II-deficient mice infected with Histoplasma capsulatum (Histoplasma) kept the fungus in check for up to 16 wk, indicating that CD8 T cells are able to limit fungal replication. Ex vivo studies showed that CD8 T cells from Histoplasma-infected mice expressed both intracytoplasmic IFN-gamma and granzyme B. Furthermore, CD8 T cells exhibited cytotoxic activity against macrophage targets containing Histoplasma. We demonstrated that the macrophage, being the primary host cell as well as the effector cell, can also serve as Ag donor to dendritic cells. Histoplasma-specific CD8 T cells are stimulated by dendritic cells that present exogenous Histoplasma Ags, either through direct ingestion of yeasts or through uptake of apoptotic macrophage-associated fungal Ags, a process known as cross-presentation. Based on these results, we present a model detailing the possible sequence of events leading to a cell-mediated immune response and fungal clearance in Histoplasma-infected hosts.