Regulation of CD8+ T cell responses to Toxoplasma gondii

Protective immunity to Toxoplasma gondii, an intracellular protozoan parasite, is characterized by a strongly polarized Th1-mediated immune response that is dependent on CD4+ and CD8+ T cells. In order to study the factors that influence development of CD8+ T cell responses to this parasite, a system was developed using a replication-deficient parasite that expressed the model antigen ovalbumin (OVA). These initial studies revealed that an OVA-specific CD8+ T cell response was induced and peaked at day 10 post-immunization, that the primary response was CD4+ T cell-dependent, and that the cells induced by immunization primarily resembled effector cells. Protective immunity to rechallenge using this model was mediated by CD8+ T cells. Long-term study of the CD8+ T cell response was undertaken, in WT mice as well as in c-Rel-/mice, which are susceptible to T. gondii infection. In these studies, c-Rel was required for optimal primary expansion of CD8+ T cells in response to T. gondii. Surprisingly, while T cells express c-Rel, it was not intrinsically required by the T cells themselves, since adoptive transfer of c-Rel-/CD8+ T cells to WT mice restored their expansion. Further examination revealed that the inflammatory environment but not the T cells themselves required expression of c-Rel, because exogenous IL-12 rescues the CD8+ T cell responses in c-Rel-/mice. Maintenance of memory CD8+ T cells as well as secondary expansion of these cells following challenge was independent of c-Rel. This work provided the first characterization of an antigen-specific memory CD8+ T cell response to non-replicating strain of T. gondii as well as showing that c-Rel is not intrinsically required by CD8+ T cells for expansion or effector function following infection, and provides new insights into the requirements for memory cell formation. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Immunology First Advisor Christopher A. Hunter