Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages

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Abstract

Helper T cells control host defense against pathogens. The receptors for interleukin 12 (IL-12), IL-4 and IL-6 are required for differentiation into the TH1, TH2 and TH17 subsets of helper T cells, respectively. IL-2 signaling via the transcription factor STAT5 controls TH2 differentiation by regulating both the TH2 cytokine gene cluster and expression of Il4ra, the gene encoding the IL-4 receptor α-chain. Here we show that IL-2 regulated TH1 differentiation, inducing STAT5-dependent expression of the IL-12 receptor β2-chain (IL-12Rβ2) and the transcription factor T-bet, with impaired human TH1 differentiation when IL-2 was blocked. TH1 differentiation was also impaired in mouse Il2−/− T cells but was restored by IL-12Rβ2 expression. Consistent with the inhibition of TH17 differentiation by IL-2, treatment with IL-2 resulted in lower expression of the genes encoding the IL-6 receptor α-chain (Il6ra) and the IL-6 signal transducer gp130 (encoded by Il6st), and retroviral transduction of Il6st augmented TH17 differentiation even when IL-2 was present. Thus, IL-2 influences helper T cell differentiation by modulating the expression of cytokine receptors to help specify and maintain differentiated states.

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Figure 1: Proliferation-dependent and proliferation-independent effects of IL-2 on TH1 differentiation.
Figure 2: IL-2 induces the expression of Il12rb2 and Tbx21 and is required for normal TH1 differentiation.
Figure 3: IL-2 induces IL12RB2 and TBX21 during human TH1 differentiation.
Figure 4: IL-2-induced, STAT5-dependent Il12rb2 expression.
Figure 5: IL-2-induced, STAT5-dependent Tbx21 expression.
Figure 6: Restoration of the TH1 differentiation of Il2−/− mice by Il12rb2 but not by Tbx21.
Figure 7: In vivo TH1 responses require IL-2.
Figure 8: Importance of IL-2 in TH17 differentiation.

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Change history

  • 20 May 2011

    In the version of this article initially published online, the labels along the horizontal axes of the graphs at right in Figure 8b,c were incorrect, and the legend for Figure 8a–c did not correctly specify the times of stimulation. The correct labels are '–' (instead of Il2+/+) and '+' (instead of Il2–/–), and the corrected legend states that the cells were "left unstimulated (–) or stimulated (+) for 4 h (a) or 24 h (b,c) with IL-2." The error has been corrected for the PDF and HTML versions of this article.

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Acknowledgements

We thank G. Robinson and L. Hennighausen (National Institute of Diabetes and Digestive and Kidney Diseases of the US National Institutes of Health) for mice with loxP-flanked Stat5a-Stat5b; K. Zhao and D. Schones for discussions; R.H. Schwartz, R. Spolski and Y. Rochman for comments; K. Cui for help in generating ChIP-Seq data; T.A. Waldmann (National Cancer Institute) for anti–human IL-2Rα (anti-Tac) and IL-2Rβ (Mikβ1); K. Murphy (Washington University St. Louis) for the pRV-Il12rb2 retroviral construct; and J. Zhu (National Institute of Allergy and Infectious Diseases of the US National Institutes of Health) for the pRV-Tbx21 construct. Supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (US National Institutes of Health).

Author information

W.L. and J.-X.L. planned studies, did experiments, analyzed data and wrote the manuscript; L.W. did experiments; P.L. analyzed data and wrote the manuscript; and W.J.L. supervised the project, planned studies, analyzed data and wrote the manuscript.

Correspondence to Warren J Leonard.

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