It is a key issue in immunology to understand how the immune system discriminates between self-and nonself, inhibiting autoimmune responses but allowing the host to mount immune responses against invading microbes (1–3). This is due to the fact that once antigen-specific lymphocytes are activated in adaptive immune responses, they exhibit essentially the same effector activity whether they respond to a microbe or to a self-constituent. That is, once aberrant immune responses (eg, autoimmune, immunopathologic, or allergic responses) are triggered, serious damage to the host may ensue because of the power of potent effector activity, high antigen specificity, and immunologic memory of adaptive immunity. There is now accumulating evidence in humans and animals that the normal immune system harbors naturally arising CD4 regulatory T (TR) cells, which play key roles in controlling such aberrant immune responses (4, 5). The majority, if not all, of naturally occurring CD4 TR cells constitutively express CD25 (IL-2 receptor chain) in the physiologic state (4, 5). At least some of them are produced by the normal thymus as a functionally mature T cell subpopulation with a broad TCR repertoire recognizing self-and nonself antigens (4). They are engaged in the maintenance of immunologic self-tolerance by actively suppressing the activation and expansion of self-reactive lymphocytes that may cause autoimmune disease. This is illustrated by the finding that the removal of CD25 CD4 T cells, which constitute 5–10% of peripheral CD4 T cells in mice, leads to spontaneous development of various autoimmune diseases in otherwise normal mice. Reconstitution of the depleted population prevents the autoimmunity (6). The removal of this population also triggers excessive or misdirected immune responses to microbial antigens, causing immunopathology. For example, depletion of TR cells elicits inflammatory bowel disease in mice due to hyperreaction of the remaining T cells to commensal bacteria in the intestine (7). Their depletion similarly precipitates severe pneumonitis in mice that are opportunistically infected with Pneumocystis carinii (8). In contrast, such treatments can enhance protective immune responses against invading microbes including bacteria, viruses, fungi, and intracellular parasites, leading to their eradication from the host (9–13). Thus, naturally occurring CD25 CD4 TR cells not only inhibit immune responses against self-antigens but also hamper or suppress those against microbes invading or cohabiting with the host. This raises a critical question: how do CD25 CD4 TR cells manage to suppress autoimmune responses or excessive antimicrobial immune responses causing immunopathology, but allow protective responses against invading pathogenic microbes?