Analyzing regulatory T cell function in a transgenic allograft model

Long-term survival of transplanted organs currently requires chronic immunosuppressive treatment of recipients. While the efficacy of these therapies is satisfactory, their toxicity to host tissues and non-specific inhibition of the immune response are disadvantageous. The ideal in transplantation is induction of donor-specific tolerance, but this has been achieved reliably only in experimental models. Accumulating evidence suggests that immunoregulatory CD4+CD25+ T cells (T-regs) are a critical component in many strategies used to effect tolerance. These cells therefore represent a potentially invaluable tool for prolonging survival of allografts. However, many aspects of T-reg function in vivo have yet to be elucidated including the mechanism of T-reg-mediated allograft prolongation.; In Chapter III, we establish a model for investigation of the mechanism of regulatory T cell-mediated allograft prolongation. This model correlates T cell proliferation in the draining lymph node with the biologically relevant readout of graft rejection in an immunocompetent host. In Chapter IV, we extend this model to characterize the mechanism by which T-regs prolong graft survival. We demonstrate that T-reg-mediated allograft prolongation is correlated with inhibition of naive T cell proliferation in the draining lymph node. These findings establish the lymph node as a potentially critical site of regulation of the allograft response. In Chapter V, we further this premise by illustrating that the lymph node is an independent site of suppression. Regulatory cells that do not encounter the allograft are capable of restricting T cell responses to alloantigen in the draining lymph node. Finally, in Chapter VI, we investigate how regulatory cells are themselves controlled in vivo. Our data indicate that innate signals transiently inhibit T-regs to allow development of the immune response, and that the interaction of GITR with the GITR ligand may be the mechanistic basis of this regulation. Studies here not only advance our understanding of T-reg-mediated allograft prolongation, but can also be generalized to model how T-regs are integrated into the immune system allowing initiation of productive immune responses yet controlling them to prevent autoimmune attack.