T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-alpha 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-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.
Tanaka
Yoshihiko
Y
Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, University, Fukuoka 812-8582, Japan.
Hamano
Shinjiro
S
Gotoh
Kazuhito
K
Murata
Yuzo
Y
Kunisaki
Yuya
Y
Nishikimi
Akihiko
A
Takii
Ryosuke
R
Kawaguchi
Makiko
M
Inayoshi
Ayumi
A
Masuko
Sadahiko
S
Himeno
Kunisuke
K
Sasazuki
Takehiko
T
Fukui
Yoshinori
Y
D000595:Amino Acid Sequence; D000818:Animals; D020690:GTPase-Activating Proteins / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000502:physiology; D008969:Molecular Sequence Data; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*; D053662:Interleukin-4 Receptor alpha Subunit
D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D015847:Interleukin-4; D011956:Receptors, Cell Surface; C471356:DOCK2 protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit