Interleukin (IL)-2 plays a crucial role in the maintenance of natural immunologic selftolerance. Neutralization of circulating IL-2 by anti–IL-2 monoclonal antibody for a limited period elicits autoimmune gastritis in BALB/c mice. Similar treatment of diabetes-prone nonobese diabetic mice triggers early onset of diabetes and produces a wide spectrum of T cell–mediated autoimmune diseases, including gastritis, thyroiditis, sialadenitis, and notably, severe neuropathy. Such treatment selectively reduces the number of Foxp3-expressing CD25 CD4 T cells, but not CD25 CD4 T cells, in the thymus and periphery of normal and thymectomized mice. IL-2 neutralization inhibits physiological proliferation of peripheral CD25 CD4 T cells that are presumably responding to normal self-antigens, whereas it is unable to inhibit their lymphopenia-induced homeostatic expansion in a T cell–deficient environment. In normal naive mice, CD25low CD4 nonregulatory T cells actively transcribe the IL-2 gene and secrete IL-2 protein in the physiological state. IL-2 is thus indispensable for the peripheral maintenance of natural CD25 CD4 regulatory T cells (T reg cells). The principal physiological source of IL-2 for the maintenance of T reg cells appears to be other T cells, especially CD25low CD4 activated T cells, which include self-reactive T cells. Furthermore, impairment of this negative feedback loop via IL-2 can be a cause and a predisposing factor for autoimmune disease.

Accumulating evidence indicates that IL-2 may contribute to the maintenance of natural immunologic self-tolerance and prevention of autoimmune disease. For example, IL-2–deficient (IL-2/) mice succumb to lethal immunopathology that includes autoimmune components (1, 2). Autoimmune disease, such as type 1 diabetes (T1D), can be prevented in animal models by IL-2 administration (3–5). Allelic variations of the IL-2 gene are associated with genetic susceptibility to T1D and experimental allergic encephalitis (EAE) in animal models (6). Furthermore, the majority of naturally arising CD4 regulatory T cells (T reg cells) express CD25, the IL-2R chain, and abnormality in their development or function leads to various