Natural and Induced CD4+CD25+ Cells Educate CD4+CD25− Cells to Develop Suppressive Activity: The Role of IL-2, TGF-β, and IL-10

Abstract

Natural and Induced CD4
CD25
Cells Educate CD4
CD25 Cells to Develop Suppressive Activity: The Role of IL-2, TGF-, and IL-101 Song Guo Zheng, Ju Hua Wang, J. Dixon Gray, Harold Soucier, and David A. Horwitz2 Thymus-derived, natural CD4
CD25
regulatory T cells can educate peripheral CD4
CD25 cells to develop suppressive activity by poorly understood mechanisms. TGF- has IL-2-dependent costimulatory effects on alloactivated naive, human CD4
T cells and induces them ex vivo to become potent contact-dependent, cytokine-independent suppressor cells. In this study, we report that CD4
CD25
cells are the targets of the costimulatory effects of IL-2 and TGF-. These cells do not divide, but, instead, greatly increase the numbers of CD4
CD25 cells that become CD25
cytokine-independent suppressor cells. These CD4
CD25
reg- ulatory cells, in turn, induce other alloactivated CD4
CD25 cells to become potent suppressor cells by mechanisms that, sur- prisingly, require both cell contact and TGF- and IL-10. The suppressive effects of these secondary CD4
CD25
cells depend upon TGF- and IL-10. Moreover, both the naive CD4
cells induced by IL-2 and TGF- to become suppressor cells, and the subsequent CD4
CD25 cells educated by them to become suppressors express FoxP3. We suggest that the long-term effects of adoptively transferred natural-like CD4
CD25
regulatory cells induced ex vivo are due to their ability to generate new cytokine- producing CD4
regulatory T cells in vivo. The Journal of Immunology, 2004, 172: 5213–5221. T regulatory (Treg)3 cells are heterogeneous T cell popula- tions that prevent harmful immune responses to self and nonself Ags. Formerly called suppressor T cells, they can be classified into two major categories: thymus-derived natural Treg cells and those induced in the periphery. The principal subset of natural regulatory cells are CD4
cells that constitutively ex- press CD25, the
-chain of the IL-2R (1–3). These have a contact- dependent, cy

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