Control of autoaggressive T cells by regulatory T cells (Treg) is essential to ensuring peripheral tolerance. Several subsets of CD4+ T cells with suppressive properties have been described, including induced T helper (Th) type 3 and T regulatory (Tr) type 1 cells and naturally occurring CD4+ CD25+ Treg. CD4+ CD25+ Treg suppress the response of conventional T cells in a cell contact-dependent manner, whereas Th3 and Tr1 cells produce immunosuppressive cytokines. Two subsets of human CD4+ CD25+ Treg, characterized by expression of the integrins α 4 β 7 or α 4 β 1, are able to convey suppressive capacity to conventional CD4+ T cells, thereby generating Th suppressor cells (Th sup). One outstanding feature is the generation of Th sup with distinct properties. α 4 β 7 Treg induce Tr1-like interleukin (IL)-10–producing Th sup, whereas α 4 β 1 Treg induce Th3-like Th sup, which produce transforming growth factor (TGF)-β. Thus, our findings reconcile contradictory results clearly demonstrating that suppression is contact dependent in vitro but mediated by soluble factors (IL-10 and TGF-β) in vivo.