| Numerous studies have highlighted the importance of high affinity interactions between T cell receptor (TCR) and their ligands in the selection of Foxp3+ regulatory T cells (Treg). To determine the role of the TCR in directing T cells into the Foxp3+ lineage, we generated transgenic (Tg) mice expressing TCRs from Foxp3+ cells. Initial analyses of the TCR Tg mice crossed with RAG-deficient mice showed that the percentage of Foxp3+ cells was very low. However, intrathymic injection and bone marrow chimera experiments showed a saturable increase of the Foxp3 + population when Treg TCR Tg cells were present in low numbers. Furthermore, when analyzing whole thymi of Treg TCR Tg RAG- deficient mice, we found significantly more Foxp3+ cells than in conventional T cell (Tconv)TCR Tg mice. Our results indicate that the TCR has an instructive role in determining Foxp3 expression; however, the size of the clonal Treg cell compartment was much smaller than clonal compartment of Tconv cells. We propose that the availability of ligands for T reg cell selection is strongly limiting and thus restricts the number of clonal Foxp3+ cells.;In the second part of the thesis, we examined the role of myelin basic protein (MBP) specific Th1 and Th17 in experimental autoimmune encephalomyelitis (EAE) pathogenesis. During the course of spontaneous EAE, we observed that large numbers of Th1 cells were found in the spinal cord before significant numbers of Th17 cells could be detected. To dissect the individual roles of Th17 and Th1 cells in EAE pathogenesis, we adoptively transferred in vitro-generated MBP-specific Th17 and Th1 cells. Th17 cells induced a non-classical (rolling) form of EAE, associated with brainstem and cerebellum inflammation. Interestingly, the majority of the T cells recovered from the CNS of Th17 cell-injected mice produced IFN-gamma, with only a small fraction producing IL-17 in lymphopenic hosts. However, when transferred into wild type hosts, Th17 cells maintained their cytokine profiles and caused non-classical EAE and classical EAE, characterized by spinal cord inflammation. Our data suggested that wild type hosts contained factors that maintain Th17 cytokine profile while lymphophenic hosts lacked such factors. |
