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

Nat Immunol. 2007 Oct;8(10):1067-75. doi: 10.1038/ni1506. Epub 2007 Sep 2.

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-4Ralpha 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-4Ralpha. Thus, Dock2 links T cell receptor signals to downregulation of IL-4Ralpha to control the lineage commitment of CD4+ T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • GTPase-Activating Proteins / physiology*
  • Interleukin-4 / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Microtubules / physiology
  • Molecular Sequence Data
  • Protein Transport
  • Receptors, Cell Surface / metabolism*
  • Th2 Cells / cytology
  • Th2 Cells / immunology*

Substances

  • DOCK2 protein, mouse
  • GTPase-Activating Proteins
  • Il4ra protein, mouse
  • Receptors, Cell Surface
  • Interleukin-4