Dendritic Cells Cross-Present Exogenous Fungal Antigens to Stimulate a Protective CD8 T Cell Response in Infection byHistoplasma capsulatum

Abstract

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-γ 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.

CD8– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

“…We here show that OVA-specific CD8 + T cells proliferate in vivo and in vitro in response to crosspresentation of yeast-OVA by DC, which is consistent with previous studies [5]. H. capsulatum infection leads to cross-presentation and a protective CD8 + T cell response in mice [53]. Furthermore, CD8 + T cell responses specific for various types of yeast are detected in humans [54].…”

Antigen-Specific CD8+ T Cells and the Development of Central Memory during Mycobacterium tuberculosis Infection

“…Because CD8 ϩ T cells that express cell surface CD107A/B have undergone degranulation, the contents of their cytotoxic granule, including granzyme B, are depleted (13,36). Although granzyme B and CD107A/B are sometimes found to be highly expressed by Ag-specific CD8 ϩ T cells, particularly after acute viral infection, the expression of these markers of CTL activity can be significantly less during chronic or persistent infection (2,37,38).…”

“…For example, identifying the CFP10 [32][33][34][35][36][37][38][39] epitope enabled us to show that CFP10-specific CD8 ϩ T cells, which accumulate in the lungs of mice following infection, have cytolytic activity in vivo (1). Elucidating the minimal epitopes presented by class I MHC allows accurate enumeration and characterization of Agspecific CD8 ϩ T cells primed during infection.…”

“…Thus, just as CFP10 [32][33][34][35][36][37][38][39] is an immunodominant epitope recognized by CD8 ϩ T cells in mice with the H-2 k haplotype (1), TB10.4 20 -28 is an immunodominant epitope in H-2 d BALB/c mice. TB10.4 20 -28 -specific CD8 ϩ T cells are found both in primary and secondary lymphoid organs, and accumulate in large numbers in the lung and in the bronchoalveolar compartment following aerosol infection with M. tuberculosis.…”

Dendritic cell interactions withHistoplasmaandParacoccidioides

“…51 The CD8 T cells were not essential for protective immunity in immunocompetent mice, but their interaction with antigen-exposed DCs activates them and accelerates clearance of the fungus in MHC II-deficient mice, effects that have been implicated in vaccination models. 52,53 Hence, there are clearly opposing rolls of CD4 and CD8 T cells in histoplasmosis, underscoring the importance of antigen presentation of DCs and their resulting regulation of IL-4 and fungal clearance. 51 A deficiency in either CD8 T cells or in MHC I has little effect on H. capsulatum clearance.…”