An increasing number of studies indicate that a subset of CD4+ T cells with regulatory capacity (regulatory T cells; T regs) can function to control organ-specific autoimmune disease. To determine whether abnormalities of thymic-derived T regs play a role in systemic lupus erythematosus, we evaluated T reg prevalence and function in (New Zealand Black× New Zealand White) F 1 (B/W) lupus-prone mice. To explore the potential of T regs to suppress disease, we evaluated the effect of adoptive transfer of purified, ex vivo expanded thymic-derived T regs on the progression of renal disease. We found that although the prevalence of T regs is reduced in regional lymph nodes and spleen of prediseased B/W mice compared with age-matched non-autoimmune mice, these cells increase in number in older diseased mice. In addition, the ability of these cells to proliferate in vitro was comparable to those purified from non-autoimmune control animals. Purified CD4+ CD25+ CD62L high B/WT regs were expanded ex vivo 80-fold, resulting in cells with a stable suppressor phenotype. Adoptive transfer of these exogenously expanded cells reduced the rate at which mice developed renal disease; a second transfer after treated animals had developed proteinuria further slowed the progression of renal disease and significantly improved survival. These studies indicate that thymic-derived T regs may have a significant role in the control of autoimmunity in lupus-prone B/W mice, and augmentation of these cells may constitute a novel therapeutic approach for systemic lupus erythematosus.