Abstract
Studies have focused on the events that influence the development of interleukin 17 (IL-17)–producing T helper cells (TH-17 cells) associated with autoimmunity, such as experimental autoimmune encephalitis, but relatively little is known about the cytokines that antagonize TH-17 cell effector responses. Here we show that IL-27 receptor–deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4+ T cell dependent and was associated with a prominent IL-17 response. In vitro, treatment of naive primary T cells with IL-27 suppressed the development TH-17 cells induced by IL-6 and transforming growth factor-β, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of IL-6 signaling mediated by the suppressor protein SOCS3. Thus IL-27, a potent inhibitor of TH-17 cell development, may be a useful target for treating inflammatory diseases mediated by these cells.
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Acknowledgements
We thank P. Scott for discussion; and R. Kastelein and D. Cua for critical comments and encouragement. Supported by the National Institutes of Health (AI42334, AI41158 and 1-T32-AI-055428), the Scholler Foundation, the State of Pennsylvania, and the National Health and Medical Research Council of Australia (M.E.).
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J.S.S. and C.A.H. contributed to all studies; E.H.W., E.H., A.V.V. and C.J.M.S. were involved in the analysis of Il27ra−/− mice; L.M.J. contributed to the studies of STAT1; Q.H. and D.S. contributed to the studies of p28; M.E. contributed to the studies of gp130Y757F mice; and A.L., C.T., J.J.O. and L.H. contributed to the studies of SOCS3.
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D.S. and Q.H. are employees of eBioscience; C.J.M.S. is an employee of Amgen; and C.A.H. and J.S.S. have applied for a patent for the use of IL-27 to modulate T cell responses.
Supplementary information
Supplementary Fig. 1
T cells isolated from the brains of chronically infected Il27ra−/− and WT mice display an activated phenotype. (PDF 83 kb)
Supplementary Fig. 2
IL-27 inhibits IL-17 production by CD4+ T cells without stimulation with PMA and ionomycin. (PDF 95 kb)
Supplementary Fig. 3
IL-27 inhibition of IL-17 production by T cells is independent of SOCS3. (PDF 79 kb)
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Stumhofer, J., Laurence, A., Wilson, E. et al. Interleukin 27 negatively regulates the development of interleukin 17–producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 7, 937–945 (2006). https://doi.org/10.1038/ni1376
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DOI: https://doi.org/10.1038/ni1376
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