The development, activation, function and mechanisms of regulatory alpha-beta-TCR+CD3+CD4-CD8-NK- T cells in the suppression of allogeneic and autologous immune responses

alphabeta-TCR+CD3+CD4- CD8- (double negative, DN) regulatory T (Treg) cells from both mice and humans have been shown to suppress autologous T cell proliferation. Transferring activated DN Treg cells to naive recipient mice enhances allo- and xenogeneic graft survival in a dose-dependent, and Ag-specific fashion. The focus of this thesis was to identify the factors determining the development, activation, function and mechanisms of DN Treg cells in immune response suppression. We show that DN T cells can develop from CD8- precursors, and in the absence of a thymus. Moreover, these DN T cells can suppress CD8+ T cell proliferation and survival in vitro. In addition, we demonstrate that activated APC are more effective at priming DN Treg cell proliferation and suppressive function than naive APC. Further, DN Treg cells possess cytotoxicity towards cognate Ag-expressing DC, but not B cells, suggesting that DN Treg cells may suppress CD8+ T cell proliferation by limiting DC survival. We also show that primary DN Treg cells can acquire allogeneic Ag in a TCR/Ag-specific fashion, and express this alloantigen on their cell surface. DN Treg cells preferentially acquire allogeneic Ag from activated B cells rather than mature DC. Finally, we show that DN Treg cells are primed by TCR-specific Ags that are presented on self-MHC, and that these DN Treg cells can suppress immune responses in vitro and inhibit autoimmune diabetes development. Taken together, the data presented within this thesis uncovers novel pathways of DN Treg cell maturation, activation and immune response suppression. Enhanced knowledge of the mechanisms leading to DN Treg cell development, proliferation and function may allow us to use DN Treg cells as an Ag-specific therapy for a vast array of immune-mediated disorders.