Abstract
Interleukin-12 (IL-12) and interferon-γ (IFN-γ) drive T helper type 1 (TH1) differentiation, but the mechanisms underlying the regulation of the complicated gene networks involved in this differentiation are not fully understood. Here we show that the IFN-γ-induced transcription factor IRF1 was essential in TH1 differentiation by acting on Il12rb1, the gene encoding the IL-12 receptor β1 subunit (IL-12Rβ1). IRF1 directly interacted with and activated the Il12rb1 promoter in CD4+ T cells. Notably, the IRF1-dependent induction of IL-12Rβ1 was essential for IFN-γ–IL-12 signaling but was dispensable for IL-23–IL-17 signaling. Because both IL-12 and IL-23 bind to and transmit signals through IL-12Rβ1, our data suggest that distinct thresholds of IL-12Rβ1 expression are required for TH1 versus TH-17 differentiation.
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Change history
13 December 2007
In the version of this supplementary file originally posted online, a band in the middle panel of Fig. 4C was not visible; the contrast has been adjusted appropriately. The error has been corrected in the PDF version of the article.
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Acknowledgements
We thank R. Flavell, R. Medzhitov, M. Feldmann, A. Rao and G. Nunez for discussions; L. Glimcher (Harvard School of Public Health) for the T-bet retrovirus vector and Tbx21−/− mice; R. Kastelein (DNAX Research Institute) for the IL-12Rβ1 bicistronic retrovirus vector; S. Hida and S. Taki (Shinshu University Graduate School of Medicine) for Rag1−/− mice; K. Ogasawara, A. Takaoka, H. Takayanagi, Y. Ohba, T. Tamura, H. Yanai, H. Katoh, C. Nakajima, K. Tsushima and H. Negishi for advice; Y. Matsuno and M. Shishido for technical assistance; D. Savitsky for critically reading the manuscript; and T. Yokochi and A. Sawa for encouragement. Supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant for Advanced Research on Cancer and a Grant-In-Aid for Scientific Research on Priority Areas), the Ishidu Shun Memorial Foundation (S.K.) and the Japan Society for the Promotion of Science (S.V.).
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S.-i.K. designed and did the experiments, analyzed the data and wrote the paper; K.S. provided some of the initial results and ideas; Y.M. did the histological analysis of colitis; S.V. and S.K. did some of the experiments and analyzed the data; K.B., K.H. and M.K. generated key materials and analyzed some of the critical data; and T.T. supervised all the work and wrote the paper.
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Kano, Si., Sato, K., Morishita, Y. et al. The contribution of transcription factor IRF1 to the interferon-γ–interleukin 12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells. Nat Immunol 9, 34–41 (2008). https://doi.org/10.1038/ni1538
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DOI: https://doi.org/10.1038/ni1538
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