Infection with T. gondii remains a serious cause of mortality in those individuals who are immunosuppressed. The cellular immune response is the principal mediator of host protection against infection. Cytolytic CD8+ T cells are an essential component of this immune response. The overall goal of the proposed research is to evaluate the long-term immune response against T. gondii. An improved understanding of the mechanisms that prevent reactivation of infection in the normal and immunocompromised host may provide for the development of novel therapeutic approaches.
The Specific Aim #1 is to evaluate the CD8+ T cell mediated cytolytic (CTL) response in normal and immunocompromised hosts to murine-acquired immunodeficiency syndrome (MAIDS). Normal and MAIDS-infected mice will be vaccinated with live, attenuated, or parasite lysate plus the novel cytokine IL-15 and the CD8+ CTL response will be evaluated. Preliminary studies suggest immunization with either attenuated parasites (ts-4) or parasite lysate plus IL-15 induces a long-term CD8+ CTL response in mice. The avidity of these CD9 cytotoxic cells for infected targets will be assessed and the efficacy of adoptive transfer into infected immunocompromised host will be evaluated. The changes in the host immune system as a result of the adoptive transfer will be studied.
Specific Aim #2 is to determine the immune factors that are important for the generation and maintenance of a protective memory CTL response in normal and MAIDS infected mice. The necessity of persistent parasite antigen exposure, CD4+ T cells, and the requirement for ILL-12 in maintaining the memory immune response will be determined. The ability of other cytokines, in particular IL-12 and IL-15, to prolong or increase the memory CTL response in the normal hosts will be studied. In the preliminary observations, loss of Toxoplasma-specific CD8+ CTL response in MAIDS-infected mice was observed. The restoration of the CTL response by in vitro culture of CD8+ T cells with cytokines will be evaluated.
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