Protective immunity to the pathogenic fungus, Histoplasma capsulatum (Hc) requires an interaction between macrophages and T cells. The latter play a pivotal role in host resistance by releasing cytokines that arm macrophages to express antifungal activity. For T cells to become activated they must recognize peptide epitopes from antigen that have been degraded by macrophages. The Histoplasma antigen HSP 60 antigens induces a cellular immune response that confers protective immunity. Two others, HSP 70 and H antigen, trigger a cellular immune response, but fail to mediate a protective immune response. These results indicate that not all antigens may stimulate protective cellular activity. The reasons for this disparity in biological activities between protective and non-protective Histoplasma antigens is not known, but this information is critically important for understanding the basis for vaccine-associated immunity. This proposal will test the hypothesis that the difference between a protective and a non-protective Histoplasma antigen is determined by the profile of cytokines generated in response to vaccination, the T cell repertoire induced by vaccination, the induction of co-stimulatory molecules on antigen-presenting cells or a combination of these processes.
Specific Aim 1 will endeavor to determine if the host response to hsp 60 differs from that of hsp 70. The following will be analyzed: i) cytokine production in lymphoid tissue; ii) inflammation to each antigen; and iii) expression of CD80 and CD86.
Specific Aim 2 will determine the functional importance of cytokines, T cells and co-stimulatory molecules and protective efficacy. The emphasis will be in determining which cytokines may be critical for hsp 60-induced immunity, the T cell populations that are necessary for the efficacy of hsp 60, the role of CD80 and CD86, and the whether the immunogenicity of rhsp 70 can be enhanced. Although hsp 60 may be protective, this proposal seeks to identify other protective antigens.
In Specific Aim 3 a new strategy will be pursued to identify new antigens that could elicit protective immunity. This strategy is based on the hypothesis that Histoplasma peptides derived from the processing of viable yeast antigens and bound to class II major histocompatibility complex (MHC) molecules are central determinants of CD4+ T cell activation.
Aim 3 will identify naturally processed peptides on class II MHC to determine their amino acid sequence, clone and express the genes encoding the peptides, and determine if they stimulate the inductive phase of T cell-mediated immune responses to Histoplasma.
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