Origin of regulatory T cells with known specificity for antigen

T cell receptor agonists can induce the differentiation of regulatory T (T-R) cells. We report here that the immunoglobulin kappa-controlled expression of an agonist in different cell types correlated with the phenotype of the generated TR cells. We found that aberrant expression on thymic stroma yielded predominantly CD4(+)CD25(+) T-R cells, which-under physiological conditions-may be induced by ectopically expressed organ-specific antigens and thus prevent organ-specific autoimmunity. Expression of the agonist antigen by nonactivated hematopoietic cells produced mostly CD4(+)CD25(-) T-R cells. This subset can be derived from mature monospecific T cells without "tutoring" by other T cells and can be generated in the absence of a functioning thymus. Suppression of CD4(+)T cell proliferative responses by both CD25(+) and CD25(-) subsets was interleukin 10 (IL-10)-independent and was overcome by IL-2. These data suggest that distinct pathways can be exploited to interfere with unwanted immune responses.