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The long-term objectives of this project are to determine the mechanisms involved in early T cell triggering by Toxoplasma gondii, and to determine the consequences of early T cell responses on subsequent pathogenesis of infection.
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Although the parasite under normal conditions induces a highly efficient immune response, amongst immunocompromised patients and congenitally infected infants T. gondii is a major opportunistic infection which can cause life-threatening disease. The studies in this proposal employ mice as an experimental animal model. </p>
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Toxoplasmosis in mice follows a similar course to that occurring in humans. Earlier work on mouse T cells has established that the parasite possesses the superantigen-like ability to trigger nonimmune T lymphocytes and induce preferential expansion of Vbeta5+ T cells, in particular those of the CD8+ subset. Associated with this expansion is release of high levels of IFN- gamma, a cytokine which is essential for protection, but which when produced in large quantities may contribute to detrimental host pathology. </p>
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This project will address the question of whether early T cell triggering for IFN-gamma production acts to the benefit or detriment of the host. </p>
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There are four specific aims of this proposal: <ol>
<li> To determine the IL-12 dependency of the Vbeta5+CD8+ response and the involvement of the latter cells in the nonpersistence of CD4+ T lymphocytes in culture, a phenomenon that may be related to the increased CD8/CD4 ratio often observed during human toxoplasmosis. </li>
<li> To evaluate the parasite's ability to induce a Vbeta5+ T cell-mediated cytokine shock response, and to determine if in vitro expanded cells induce a similar response, or whether they possess a protective capability.</li>
<li> To determine if virulent and avirulent parasite strains possess the ability to preferentially expand specific Vbeta families and/or CD8+ cells during primary culture. This may be related to the variable pathology associated with different parasite strains in mice and humans. </li>
<li> To biochemically characterize and purify the parasite molecule responsible for preferential triggering of Vbeta5+CD8+ T lymphocytes. </li></ol></p>
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These specific aims will be accomplished by employing techniques of cell separation and depletion, flow cytometric analyses, polymerase chain reaction amplification of cytokine mRNA, and protein immunochemistry. </p>