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

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.