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Priming for T helper type 2 differentiation by interleukin 2–mediated induction of interleukin 4 receptor α-chain expression

Abstract

T helper type 2 (TH2) cells are essential for humoral immunity and host defense. Interleukin 4 (IL-4) drives TH2 differentiation and IL-2 augments the accessibility of Il4 chromatin. Here we demonstrate that IL-2, by inducing binding of STAT5 to the Il4ra locus, which encodes IL-4 receptor α-chain (IL-4Rα), was essential for inducing and maintaining IL-4Rα expression. Although IL-4 induced IL-4Rα expression, T cell receptor–induced IL-4Rα expression was normal in Il4−/− cells but was much lower in Il2−/− cells. Notably, forced IL-4Rα expression restored the TH2 differentiation of Il2−/− cells. Moreover, genome-wide mapping by chromatin immunoprecipitation coupled with sequencing showed broad interaction of the transcription factors STAT5A and STAT5B with genes associated with TH2 differentiation. Our results identify a previously unappreciated function for IL-2 in 'priming' T cells for TH2 differentiation and in maintaining the expression of Il4ra and other genes in TH2-committed cells.

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Figure 1: IL-2 potently induces IL-4Rα expression.
Figure 2: IL-2-induced IL-4Rα expression is independent of IL-4.
Figure 3: STAT5-dependent regulation of IL-4Rα expression.
Figure 4: Analysis of STAT5-binding sites in human IL4R.
Figure 5: Binding of STAT5 to the Il4ra and Il4 loci.
Figure 6: IL-2 is important for TCR-induced IL-4Rα expression.
Figure 7: The extent of IL-4Rα expression influences TH2 cell differentiation.
Figure 8: Retrovirus-mediated expression of IL-4Rα restores the TH2 differentiation of Il2−/− CD4+ T cells.
Figure 9: STAT5-activating cytokines other than IL-2 can increase IL-4Rα expression.

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Acknowledgements

We thank P. Ryan (National Heart, Lung and Blood Institute, National Institutes of Health) for Il4−/− mice; J.X. Lin (National Heart, Lung and Blood Institute, National Institutes of Health) for discussions and real-time PCR primers; J.F. Zhu, H.H. Xue, H.P. Kim and R. Spolski for discussions and technical assistance; L. Hennighausen for support and discussions; and X. Shirley Liu for the 'model-based analysis of ChiP-seq' algorithm. Supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute, National Institutes of Health.

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W.L. designed and did research, analyzed data, and wrote the paper; D.E.S. analyzed data and wrote the paper; J.O., Y.C., K.C. and T.Y.R. did research; K.Z. analyzed data; W.J.L. designed research, analyzed data and wrote the paper; and all authors reviewed the paper before submission.

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Correspondence to Warren J Leonard.

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Liao, W., Schones, D., Oh, J. et al. Priming for T helper type 2 differentiation by interleukin 2–mediated induction of interleukin 4 receptor α-chain expression. Nat Immunol 9, 1288–1296 (2008). https://doi.org/10.1038/ni.1656

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