Interleukin-2-deficient mice (IL-2−/−) crossed to a BALB/c genetic background develop a lymphoproliferative syndrome with severe hemolytic anemia and die within 5 weeks of age. The presence of autoantibodies of various specificities and inflammatory lesions in several organs are indicative of a generalized autoimmune disease. No alterations of the immune system were observed in 6-day-old animals, but 10-day-old mice already showed an increased proliferation and polyclonal activation of lymphocytes. The treatment of IL-2−/− mice with anti-gp39(CD40L) antibody prevented the disease and indicated that the appearance of activated CD4+ T cells (CD44high, CD69+) represents the first alteration of the immune system in IL-2−/− mice. Collectively, our results suggest that an essential role of IL-2 in vivo, which is not compensated by other cytokines, is the maintenance of self tolerance.