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Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

Abstract

On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (TH) cells are traditionally thought to differentiate into TH1 and TH2 cell subsets. TH1 cells are necessary to clear intracellular pathogens and TH2 cells are important for clearing extracellular organisms1,2. Recently, a subset of interleukin (IL)-17-producing T (TH17) cells distinct from TH1 or TH2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury3,4,5. In contrast, CD4+CD25+Foxp3+ regulatory T (Treg) cells inhibit autoimmunity and protect against tissue injury6. Transforming growth factor-β (TGF-β) is a critical differentiation factor for the generation of Treg cells7. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation8,9, completely inhibits the generation of Foxp3+ Treg cells induced by TGF-β. We also demonstrate that IL-23 is not the differentiation factor for the generation of TH17 cells. Instead, IL-6 and TGF-β together induce the differentiation of pathogenic TH17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (TH17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.

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Figure 1: Inhibition of T reg development by different cytokines.
Figure 2: Cytokines required for the generation of T H 17 cells.
Figure 3: Reciprocal expression of Foxp3 and IL-17 in T cells during differentiation.
Figure 4: Enhanced IL-17 production by T cells and CNS autoimmunity in TGF-β transgenic mice.

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Acknowledgements

We thank R. A. Sobel for histological analysis of CNS tissues from mice, D. Kozoriz for cell sorting, and A. Jäger for technical assistance. This work was supported by grants from the National Multiple Sclerosis Society, the National Institutes of Health, JDRF Center for Immunological Tolerance at Harvard and the Deutsche Forschungsgemeinschaft.

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Correspondence to Mohamed Oukka or Vijay K. Kuchroo.

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Supplementary information

Supplementary Figure 1

Induction of Th-IL-17 cells by activation of naive CD4+ T cells with plate bound anti-CD3 plus anti-CD28 in the presence of TGF-β and IL-6. (PDF 462 kb)

Supplementary Figure 2

IL-6 deficient mice are resistant to the development of EAE and fail to generate Th-IL-17 cells. (PDF 520 kb)

Supplementary Figure Legends

Text to accompany the above Supplementary Figures (DOC 20 kb)

Supplementary Table 1

Histological Analysis of the CNS from 2D2 and 2D2xTg TGF-b with EAE (XLS 17 kb)

Supplementary Methods

This file contains additional details on the methods used in this study. (DOC 30 kb)

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Bettelli, E., Carrier, Y., Gao, W. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006). https://doi.org/10.1038/nature04753

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