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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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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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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