Murine autoimmune gastritis, induced by neonatal thymectomy or the injection of CD25-depleted lymphocytes into nu/nu recipients, is characterized by an inflammatory infiltrate into the gastric mucosa, parietal cell destruction and circulating anti-parietal cell antibodies. Using RAG-2^−/−mice as recipients, we determined that the induction of disease relies on CD4⁺CD25⁻effector cells and prevention relies on CD4⁺CD25⁺regulatory cells; neither requires participation of CD8 cells or B cells. The severity of gastritis was dependent on the cytokine repertoire of CD4⁺CD25⁻effector T cells. Recipients of IL-4^−/−T cells developed more severe gastritis and recipients of INF-γ^−/−T cells developed milder disease than recipients of wildtype or IL-10^−/−effector T cells. Gastritis did not develop in the absence of IL-12. Protection from gastritis does not require either IL-4 or IL-10 because CD4⁺CD25⁺cells from IL-4^−/−or IL-10^−/−mice completely abrogated the disease process. CD4⁺CD25⁺cells also protected RAG-2^−/−recipients from colitis and inhibitory activity was partially dependent on IL-10 expression. These findings highlight the critical role of CD4⁺CD25⁺regulatory T cells in protection from several autoimmune syndromes and delineate the differential contribution of IL-10 to CD4⁺CD25⁺Treg activity in the settings of gastritis and colitis.