UC Riverside

T cells form a fundamental component of the protective response to chronic Toxoplasma gondii infection. The dire consequences of a failed T cell response in the protective response to this parasite are particularly apparent in AIDS patients, yet there must be a highly coordinated balance to the T cell response in the CNS. First, there must be a balance between pro-inflammatory and anti-inflammatory responses. Next, in a context of persistent antigen there must be a balance between the function of memory and effector subsets that simultaneously occupy the same niche. Finally, the T cell response must adapt to local conditions within the tissue. This dissertation explores these phenomena in the following ways:

In Chapter 1, we discuss what is known about the T cell response to Toxoplasma gondii infection. We explore the signals that determine infiltration into the brain, behavior within the brain, and phenotypic diversity. In Chapter 2, we discuss the role of tissue resident memory T cells in the protective response to chronic Toxoplasma gondii infection. Here we use RNA-Seq to determine that the distinct transcriptional profile of brain infiltrating CD103+ CD8 T cells is consistent with tissue resident memory T cells, or TRM. We then use re-stimulation assays to establish that this population has a significantly increased capacity to produce pro-inflammatory cytokines as compared to other populations within the brain. This data supports the presence of a functional population of memory T cells in the response to chronic Toxoplasma gondii infection.

In Chapter 3, we examine the requirement of lymph node homing dendritic cells expressing CCR7 for maintenance of effector T cells within the brain. This supports the requirement for ongoing recruitment of brain-infiltrating effector T cells. In Chapter 4 we examine how glutamate dysregulation within the CNS during chronic T. gondii infection impacts cytokine production and proliferation in activated T cells. We conclude in Chapter 5 by examining the common themes that emerge from the three primary chapters of the dissertation.