The role of the combination of IL‐2 and TGF‐β or IL‐10 in the generation and function of CD4(+) CD25(+) and CD8(+)regulatory T cell subsets

Horwitz, David A.; Zheng, Song Guo; Gray, J. Dixon

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 β (TGF‐β) 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 TGF‐β and IL‐10 induce peripheral T cells to produce immunosuppressive levels of each of these cytokines. This effect of TGF‐β is IL‐2 dependent. Under other conditions IL‐2 and TGF‐β can 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 cytokine‐producing 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.