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T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-α subunit controlled by the Rac activator Dock2

Abstract

The lineage commitment of CD4+ T cells is coordinately regulated by signals through the T cell receptor and cytokine receptors, yet how these signals are integrated remains elusive. Here we find that mice lacking Dock2, a Rac activator in lymphocytes, developed allergic disease through a mechanism dependent on CD4+ T cells and the interleukin 4 receptor (IL-4R). Dock2-deficient CD4+ T cells showed impaired antigen-driven downregulation of IL-4Rα surface expression, resulting in sustained IL-4R signaling and excessive T helper type 2 responses. Dock2 was required for T cell receptor–mediated phosphorylation of the microtubule-destabilizing protein stathmin and for lysosomal trafficking and the degradation of IL-4Rα. Thus, Dock2 links T cell receptor signals to downregulation of IL-4Rα to control the lineage commitment of CD4+ T cells.

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Figure 1: Excessive TH2 immune responses in Dock2−/− C57BL/6 mice.
Figure 2: Dock2 deficiency causes allergic disease in BALB/c mice.
Figure 3: Dock2−/− naive CD4+ T cells produce excessive IL-4 after antigen stimulation.
Figure 4: Dock2 acts through Rac to promote IL-4Rα downregulation.
Figure 5: Dock2 regulates the intracellular trafficking of IL-4Rα.
Figure 6: Dock2 downregulates IL-4Rα through microtubule dynamics.

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Acknowledgements

We thank A. Sobel (Institut National de la Santé et de la Recherche Médicale U706) for antibodies to phosphorylated stathmin and M. Kubo (Research Center for Allergy and Immunology, RIKEN Yokohama Institiute) for Il4ra−/− BALB/c mice. Supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (for the Genome Network Project and the Target Protein Project; Y.F.), the Precursory Research for Embryonic Science and Technology program of the Japan Science and Technology (Y.F.), Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology of Japan (Y.T. and Y.F.), the Toray Science Foundation (Y.F.) and the ONO Medical Research Foundation (Y.F.).

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Y.T. did experiments, analyzed data and contributed to manuscript preparation; S.H. did experiments and analyzed data; K.G., Y.M., Y.K., A.N., R.T., M.K. and A.I. did experiments; S.M., K.H. and T.S. interpreted data; and Y.F. designed experiments, analyzed and interpreted data and wrote the manuscript.

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Correspondence to Yoshinori Fukui.

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Tanaka, Y., Hamano, S., Gotoh, K. et al. T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-α subunit controlled by the Rac activator Dock2. Nat Immunol 8, 1067–1075 (2007). https://doi.org/10.1038/ni1506

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