CD8 T 細胞在宿主防禦組織胞漿菌感染的功能

Abstract

It is widely accepted that cellular immune response via the activation of CD4+ T cells plays an important role in the protection against endosomal intracellular non-viral pathogens of the macrophage. In HIV infection, the major complication of the disease is the progressive loss of CD4+ T cells. The infected individuals develop AIDS and succumb to opportunistic infections. It is, therefore, important to understand how CD8+ T cells function in the absence of CD4+ T cells. First of all, I enumerated antigen-specific functional T cells, which are critical to host defense against infection, in the infection of Histoplasma capsulatum, an intracellular pathogen of the macrophages. I found that not only CD4 but also CD8 T cells were activated. The magnitude of CD8 T cell response was lower than CD4 T cell, but the expansion and contraction of both cell types followed the same kinetics. Strong correlation between IFNγ production and CD44hi expression was observed not only at the peak of response but also throughout the course of infection. Moreover, a broad spectrum of Vβ populations responded to systemic as well as pulmonary infections, suggesting no obvious T cell receptor bias in primary immune response to histoplasmosis. Interestingly, after high dose challenge or secondary infection the functional T cells had a narrower TCR Vβ repertoire than do primary effector cells. 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 delays but does not affect fungal clearance. However, it remains to be determined whether the CD8 T cells are protective in a host lacking functional CD4 T cells. I found that MHC class II-deficient mice infected with Histoplasma kept the fungus in check for up to 16 weeks, indicating CD8 T cells are able to limit fungal replication but unable to clear the fungus. Ex vivo studies showed that CD8 T cells from Histoplasma-infected wild type mice exhibit cytotoxic activity as well as IFNγ production. However, the CD8 T cells in IIKO mice had functional limitation to clear systemic as well as pulmonary histoplasmosis. It is also demonstrated in this study that the macrophage, being the primary host cell as well as the effector cell of Histoplasma, can also serve as antigen donor to dendritic cells. Histoplasma-specific CD8 T cells are stimulated by dendritic cells that present exogenous Histoplasma antigens, either through direct ingestion of yeasts or through uptake of apoptotic macrophage-associated fungal antigens, a process known as ‘cross-presentation’. Based on these results, I present a model detailing the possible sequence of events leading to a cell-mediated immune response and fungal clearance in Histoplasma-infected hosts.