Human CD25(+)CD4(+) T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function

Active suppression by T regulatory (Tr) cells plays an important role in th e downregulation of T cell responses to foreign and self-antigens. Mouse CD 4(+) Tr cells that express CD25 possess remarkable suppressive activity in vitro and in autoimmune disease models in vivo. Thus far, the existence of a similar subset of CD25(+)CD4(+) Tr cells in humans has not been reported. Here we show that human CD25(+)CD4(+) Tr cells isolated from peripheral bl ood failed to proliferate and displayed reduced expression of CD40 ligand ( CD40L), in response to T cell receptor-mediated polyclonal activation, but strongly upregulated cytotoxic T lymphocyte-associated antigen (CTLA)-4. Hu man CD25(+)CD4(+) Tr cells also did not proliferate in response to allogene ic antigen-presenting cells, but they produced interleukin (IL)-10, transfo rming growth factor (TGF)-beta, low levels of interferon (IFN)-gamma, and n o IL-4 or IL-2. Importantly, CD25(+)CD4(+) Tr cells strongly inhibited the proliferative responses of both naive and memory CD4(+) T cells to alloanti gens, but neither IL-10, TGF-beta, nor CTLA-4 seemed to be directly require d for their suppressive effects. CD25(+)CD4(+) Tr cells could be expanded i n vitro in the presence of IL-2 and allogeneic feeder cells and maintained their suppressive capacities. These findings that CD25(+)CD4(+) Tr cells wi th immunosuppressive effects can be isolated from peripheral blood and expa nded in vitro without loss of function represent a major advance towards th e therapeutic use of these cells in T cell-mediated diseases.