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TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology

Abstract

Studies have shown that transforming growth factor-β (TGF-β) and interleukin 6 (IL-6) are required for the lineage commitment of pathogenic IL-17-producing T helper cells (TH-17 cells). Unexpectedly, here we found that stimulation of myelin-reactive T cells with TGF-β plus IL-6 completely abrogated their pathogenic function despite upregulation of IL-17 production. Cells stimulated with TGF-β plus IL-6 were present in the spleen as well as the central nervous system, but they failed to upregulate the proinflammatory chemokines crucial for central nervous system inflammation. In addition, these cells produced IL-10, which has potent anti-inflammatory activities. In contrast, stimulation with IL-23 promoted expression of IL-17 and proinflammatory chemokines but not IL-10. Hence, TGF-β and IL-6 'drive' initial lineage commitment but also 'restrain' the pathogenic potential of TH-17 cells. Our findings suggest that full acquisition of pathogenic function by effector TH-17 cells is mediated by IL-23 rather than by TGF-β and IL-6.

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Figure 1: IL-23 and/or TGF-β plus IL-6 enhances IL-17 production, but TGF-β plus IL-6 abrogates pathogenic function.
Figure 2: Phenotypic analysis of TH-17 cells stimulated with IL-23 or with TGF-β and IL-6.
Figure 3: In vivo fate of cells stimulated with IL-23 or with TGF-β and IL-6.
Figure 4: TGF-β plus IL-6 inhibit the production of proinflammatory chemokines by TH-17 cells.
Figure 5: TGF-β plus IL-6 promotes IL-10 production.
Figure 6: Production of IL-10 dependent on TGF-β and IL-6 mediates bystander suppression of pathogenic TH-17 cells.

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Acknowledgements

We thank B. Desai and S. Jungers for assistance with flow cytometry; J. Mattson for real-time PCR data; B. Joyce-Shaikh for technical assistance; and R. Kastelein for comments.

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M.J.M. designed and did all experiments and prepared the manuscript; K.S.B.-J. assisted with in vitro experiments; Y.C. and C.M.T. assisted with in vivo experiments; W.B. and T.M. did quantitative PCR analysis; and D.J.C. did cerebroventricular injections, supervised the studies and preparation of the manuscript.

Corresponding author

Correspondence to Daniel J Cua.

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The authors are employed by or were previously employed by Schering-Plough Biopharma.

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McGeachy, M., Bak-Jensen, K., Chen, Y. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology. Nat Immunol 8, 1390–1397 (2007). https://doi.org/10.1038/ni1539

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