Date of Award
Doctor of Philosophy (PhD)
Christopher A. Hunter
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.
Jordan, Kimberly A., "Regulation of CD8+ T cell responses to Toxoplasma gondii" (2010). Publicly Accessible Penn Dissertations. Paper 113.