RAPID COMMUNICATION The role of the combination of IL-2 and TGF- or IL-10 in the generation and function of CD4 CD25 and CD8 regulatory T cell subsets

Recently, considerable attention has been focused on thymus-derived CD4 regulatory T cells that constitutively express CD25 and have a contact-dependent, cytokine-independent mechanism in vitro. However, peripheral CD4 and CD8 T cells can also be induced to become regulatory T cells. Here we review our studies using the combination of IL-2 and transforming growth factor (TGF) to generate regulatory T cell subsets ex vivo, and the work of others using IL-10 to induce suppressive activity. Under certain conditions, the autocrine effects of TGFand IL-10 induce peripheral T cells to produce immunosuppressive levels of each of these cytokines. This effect of TGFis IL-2 dependent. Under other conditions IL-2 and TGFcan induce CD4 cells to develop potent contact-dependent, cytokine-independent regulatory activity. At present, there is considerable confusion concerning the mechanism of action of CD4 CD25 cells because cytokineproducing regulatory T cells generated in the periphery can express CD25 and other markers displayed by naturally occurring, thymus-derived regulatory T cells. We, therefore, propose a nomenclature that identifies thymus-derived and peripheral regulatory cells, and that also differentiates T regulatory cells from T helper cells. Because T regulatory cells broadly control T helper cell reactivity, the mechanisms that control regulatory cell function are also reviewed. Finally, the potential use of regulatory T cells generated ex vivo as an adoptive immunotherapy for certain autoimmune diseases, to prevent organ graft rejection, or to prevent pathologic host responses to infectious agents is discussed. J. Leukoc. Biol. 74: 471–478; 2003.