Editors' ChoiceT Cell Fate

The TCR in the Dock

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Science's STKE  02 Oct 2007:
Vol. 2007, Issue 406, pp. tw353
DOI: 10.1126/stke.4062007tw353

The Rho family guanosine triphosphatase Rac regulates the actin cytoskeleton and microtubule dynamics. Tanaka et al. investigated a role for Dock2, a guanine nucleotide exchange factor and activator of Rac in the regulation of CD4+ T cell differentiation. The authors first established that deficiency in Dock2 in mouse CD4+ T cells resulted in increased T helper 2 (TH2) responses, such as secretion of interleukin-4 (IL-4). Antigenic stimulation of Dock2–/– CD4+ T cells produced a higher proportion of TH2 cells than did similar stimulation of Dock2+/+ cells, whose response was dependent on IL-4. IL-4 signaling is necessary both for stimulating TH2 differentiation and for inhibiting TH1 differentiation. Flow cytometry revealed that, whereas T cell receptor (TCR) stimulation of Dock2+/+ CD4+ T cells resulted in a gradual loss of the IL-4 receptor α subunit (IL-4Rα) from the cell surface, this response was inhibited in Dock2–/– cells. Treatment of Dock2–/– CD4+ T cells with a cell-permeable dominant negative Rac mutant inhibited the TCR-stimulated decrease in IL-4Rα abundance. Western blotting showed that TCR stimulation of Dock2–/– CD4+ T cells resulted in increased and more sustained phosphorylation of signal transducer and activator of transcription 6 (STAT6), a downstream target of IL-4Rα that is necessary for TH2 differentiation. Confocal microscopy showed that TCR stimulation of Dock2+/+ CD4+ T cells resulted in the Rac-dependent internalization of the IL-4Rα and its degradation in lysosomes, and this process was inhibited in Dock2–/– cells. Together these data suggest a new mechanism by which the TCR regulates T cell differentiation. TCR signals through Dock2 and Rac leading to the internalization of IL-4Rα would inhibit IL-4-stimulated TH2 differentiation and thus favor TH1 differentiation.

Y. Tanaka, S. Hamano, K. Gotoh, Y. Murata, Y. Kunisaki, A. Nishikimi, R. Takii, M. Kawaguchi, A. Inayoshi, S. Masuko, K. Himeno, T. Sasazuki, Y. Fukui, 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). [PubMed]

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