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Interleukin 27 negatively regulates the development of interleukin 17–producing T helper cells during chronic inflammation of the central nervous system

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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Figure 1: Expression of IL-27 in the brain during toxoplasmic encephalitis.
Figure 2: IL-27 is required for resistance to chronic toxoplasmic encephalitis.
Figure 3: Depletion of CD4+ T cells 'rescues' Il27ra−/− mice and reduces inflammation in the brain.
Figure 4: IL-27 inhibits production of IL-17 in the brains of mice chronically infected with T. gondii.
Figure 5: IL-27 inhibits production of IL-17 by in vitro generated TH-17 cells.
Figure 6: IL-27-mediated inhibition of IL-17 production by T cells is independent of SOCS3.
Figure 7: IL-27-mediated inhibition of IL-17 production by T cells is dependent on STAT1 but not T-bet.

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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.).

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Christopher A Hunter.

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Competing interests

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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