Oral tolerance is mediated by multiple mechanisms such as anergy and/or active suppression of antigen-specific effector T cells by T regulatory (Tr) cells. Among the CD4(+) Tr cells, T regulatory type 1 cells (Tr1) have been shown to downmodulate immune responses through production of the immunosuppressive cytokines IL-10 and TGF-beta. Human Tr1 cells can be induced to differentiate in vitro by IL-10 1 IFN-alpha or after stimulation by immature dendritic cells (DCs) or DCs rendered tolerogenic by exposure to immunomodulatory compounds. Murine Tr1 cells can be induced to differentiate in vitro by activating naive CD4(+) T cells in the presence of high doses of IL-10. Several protocols for induction of oral tolerance, including oral administration of the antigen with IL-10, have been shown to induce antigen-specific Tr1 cells that suppress undesired immune responses toward self-antigens, allergens, and food antigens. Overall, these data demonstrate that IL-10-producing Tr1 cells play a central role in the induction of oral as well as systemic tolerance.