Cutting Edge: Foxp3+CD4+CD25+ Regulatory T Cells Induced by IL-2 and TGF-β Are Resistant to Th17 Conversion by IL-6

Abstract

CUTTING EDGE IMMUNOLOGY THE OF JOURNAL Cutting Edge: Foxp3
CD4
CD25
Regulatory T Cells Induced by IL-2 and TGF- Are Resistant to Th17 Conversion by IL-61 Song Guo Zheng,2 Juhua Wang, and David A. Horwitz2 TGF- has pleiotropic effects on T cell differentiation that are determined by other cytokines in the local envi- ronment. Whereas IL-2 and TGF- induce naive T cells to become forkhead/winged helix transcription factor (Foxp3) positive regulatory cells (iTregs), the combination of IL-6 and TGF- induces IL-17-producing cells (Th17). Moreover, IL-6 can use TGF- produced by thy- mus-derived natural regulatory T cells (nTregs) to convert them to Th17 cells. In this study, we report a major dif- ference between iTregs and nTregs. Treatment of iTregs with IL-6 did not affect Foxp3 expression, and their sup- pressive activity in vitro and in vivo was intact. To ex- plain this difference between nTregs and iTregs, we found that IL-2 and TGF- down-regulate IL-6 receptor ex- pression and IL-6 signaling. The resistance of iTregs to Th17 conversion suggests that they can function more ef- fectively than nTregs in an inflammatory milieu and em- phasizes the central role of IL-2 in combination with TGF- to maintain immunologic homeostasis. The Journal of Immunology, 2008, 180: 7112–7116. A ntigen-activated naive T cells can become either effec- tor cells that protect the host from harmful microbial pathogens or regulatory/suppressor cells that main- tain immunologic homeostasis and prevent autoimmunity. It has become evident that cytokines such as TGF-
can promote both effector and regulatory cell differentiation pathways de- pending upon other cytokines present in the local environment. T cells activated with IL-2 and TGF-
become forkhead/ winged helix transcription factor (Foxp3)3 positive regulatory T cells (1, 2), whereas activation with IL-6 and TGF-
results in Th17 cells (3–6). The control of these opposite differentiation pathways is not well understood and is a

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