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-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.

p27kip1 Controls Cell Morphology and Motility by Regulating Microtubule-Dependent Lipid Raft Recycling

“…Interestingly, stathmin activity also has been linked to vesicular trafficking regulation in T-helper cells, where it contributes to the control of interleukin-4 receptor recycling (44), thus independently confirming our findings. The data reported by Tanaka et al for T cells (44) and by others for neurons (46), along with our present and previous observations (2, 3), suggest that the activation of stathmin and that of small GTPases are strongly connected. It is conceivable that, at least during the first phases of cell-ECM contact, a regulatory loop exists in order to maintain a balanced activity of these different players, with increased stathmin activity leading to increased RhoA activation and increased RhoA activation stabilizing the MT network after cell adhesion (36).…”

“…In fact, the roles reported so far for p27 are pleiotropic and sometimes contrasting: it has been described as either an inhibitor or stimulator of motility (2,5,6,18,31) and tumor suppressor or oncogene (4,7,15,16,33). Interestingly, stathmin activity also has been linked to vesicular trafficking regulation in T-helper cells, where it contributes to the control of interleukin-4 receptor recycling (44), thus independently confirming our findings. The data reported by Tanaka et al for T cells (44) and by others for neurons (46), along with our present and previous observations (2, 3), suggest that the activation of stathmin and that of small GTPases are strongly connected.…”

Yersinia enterocolitica differentially modulates RhoG activity in host cells

“…RhoG may exclusively act through its close relative Rac1 for mediating bacteria-induced cell responses. However, RhoG may also have an individual function in bacterial invasion given the reported Rac1-independent RhoG effects on the cytoskeleton (Meller et al, 2008) and on intracellular vesicle transport (Prieto-Sanchez et al, 2006;Tanaka et al, 2007).…”

Gel-Free Proteome Analysis Isotopic Labelling Vs. Label-Free Approaches for Quantitative Proteomics

“…In addition, slight differences were also observed for proteins related to cellular trafficking. As T cell cellular trafficking is already known to be important for T cell differentiation (Tanaka et al, 2007), the validation of these observations is essential. We are focusing our efforts on a microtubule (Mi) polymerisation factor for which only a slight increase of abundance could be observed in IL6-activated T cells.…”