Regulatory T cells in CD4+ T cell-mediated autoimmune diseases: Contribution to the disease development and application in the disease prevention

CD4+ T cells play a critical role in the maintenance of homeostasis through generating distinct subsets of effector T cells (Teff cells) and regulatory T cells (Treg cells). Both environmental and genetic factors are thought to contribute to the balance between Teff cells and Treg cells. Part I of this thesis examines the intrinsic mechanisms regulating the development of a CD4+ T-cell-mediated spontaneous experimental autoimmune encephalomyelitis (sEAE). We observed that an ageassociated development of sEAE correlates with a decline in both the functional capacity of natural Treg cells (nTreg cells) and in PLP139-151-induced IL-10 production and a concomitant increase in IL-17 production. Anti-CD25-induced inactivation of nTreg cells increased the incidence and severity of sEAE. Conversely, induction of peripheral tolerance inhibited the development of the clinical disease concomitant with increased production of IL-10 and conversion of Foxp3 + Treg cells from CD4+CD25- progenitors. These data indicate that heterogeneous populations of Treg cells regulate the onset of sEAE, and that induction of peripheral tolerance can be exploited to prevent or treat spontaneous autoimmune disease.;Upon the findings in Part I, we next explore the application of Treg cells in autoimmune diseases. Given the small cell number of nTreg cells in the circulation and the lack of signature markers for IL-10 producing Tr1 cells, it is therefore necessary to explore alternatives to nTreg cells and Tr1 cells for Treg-based clinical treatment. Part II first optimizes an in vitro system to generate substantial numbers of PLP139-151 -specific TGF-beta-iTreg cells and then investigates the possibility of in vivo specific suppression by these cells using the conventional relapsing-remitting EAE (RR-EAE) model in which the CD4 + responder T cells with various specificities are assessed. We observed that PLP139-151-specific TGF-beta-iTreg cells express an intermediate level of CD62L and a high level of CD103, which together are a phenotype of effector/memory Treg cells and hypothetically lead the Treg cells to inflamed tissues. Furthermore, we observed that these cells could home to and proliferate in local draining lymph nodes (dLN) where they successfully inhibit the sensitization of naive T cells and the resulting disease development in an Ag-specific manner. Taken together, this thesis not only demonstrates that Treg cells are an intrinsic factor influencing the initiation of sEAE, but also implies that, by manipulating the self-Ag specific Treg cells, it is possible to prevent autoimmune diseases in predisposed individuals without inducing pan-suppression.