Protection against autoimmunity in nonlymphopenic hosts by CD4+ CD25+ regulatory T cells is antigen-specific and requires IL-10 and TGF-β

CD4(+)CD25(+) regulatory T cells (T-Reg) play a critical role in the control of autoimmunity. However, little is known about how T-Reg suppress self-reactive T cells in vivo, thus limiting the development of T-Reg-based therapy for treating autoimmune diseases. This is in large part due to the dependency on a state of lymphopenia to demonstrate T-Reg-mediated suppression in vivo and the unknown Ag specificity of T-Reg in most experimental models. Using a nonlymphopenic model of autoimmune pneumonitis and T-Reg with known Ag specificity, in this study we demonstrated that these T-Reg can actively suppress activation of self-reactive T cells and protect mice from fatal autoimmune pneumonitis. The protection required T-Reg with the same Ag specificity as the self-reactive T cells and depended on IL-10 and TGF-beta. These results suggest that suppression of autoimmunity by T-Reg in vivo consists of multiple layers of regulation and advocate for a strategy involving Ag-specific T-Reg for treating organ-specific autoimmunity, because they do not cause generalized immune suppression.