Regulation of T helper cells responses: Mechanisms for development of IL-10-producing regulatory T cells using immunosuppressive drugs

日本免疫学会総会の機会に来日されるDr. Anne O'Garraに以下の内容でご講演いただきます。ふるってご参加をお願いいたします。

CD4+ T cells may be subdivided into the T helper (Th) 1 and Th2 subsets which produce distinct profiles of cytokines and have distinct functions in the immune response. Th1 cells producing IFN-γ are important in the clearance of intracellular pathogens but can also mediate autoimmune pathologies. Th2 cells producing IL-4, IL-5 and IL-13 play a role in the clearance of extracellular pathogens but in addition mediate allergic manifestations. There is increasing evidence to support the existence of another distinct subset of CD4+ T cells with regulatory capacity that can downregulate both Th1 and Th2 type responses. Such regulatory T cells have been shown to downregulate pathology-inducing immune responses in a large number of in vivo models of autoimmunity and transplantation, at least in part via the action of TGF-β and IL-10. However, thus far it has not been possible to obtain a homogeneous population of such regulatory T cells in large numbers since the signals/stimuli involved in the differentiation of naive T cells into regulatory T cells are unknown. We now define a novel approach to differentiate naive T cells into regulatory cells in vitro by using a combination of immunosuppressive drugs which are known to affect cytokine production by T cells. Using this approach, we can generate a homogeneous population of T cells with strong regulatory capacity. This T regulatory population prevents the induction of Experimental Autoimmune Encephalomyelitis (EAE) and produces IL-10 but not IL-2, IL-4, IL-5 and IFN-γ. Furthermore, we can greatly enhance the development and the expansion of these regulatory T cells producing only IL-10 by simultaneously blocking Th1 and Th2 differentiation. Such regulatory T cells were obtained in human as well as mouse systems. The possible role of IL-4, IL-10 and TGF-β on the development and the function of these regulatory cells was also investigated. In summary, we demonstrate that a combination of immunosuppressive drugs can induce a novel homogeneous subset of CD4+ T cells distinct from Th1 and Th2 cells, which produces only IL-10 and has strong regulatory capacity. Our findings have important implications for therapeutic intervention in autoimmune diseases and transplantation, since we are now able to reproducibly generate a homogeneous population of such antigen-specific regulatory T cells.