T Cell Fate The TCR in the Dock

John F. Foley

Science’s STKE, AAAS, Washington, DC 20005, USA

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 (T_H2) responses, such as secretion of interleukin-4 (IL-4). Antigenic stimulation of Dock2^–/– CD4⁺ T cells produced a higher proportion of T_H2 cells than did similar stimulation of Dock2^+/+ cells, whose response was dependent on IL-4. IL-4 signaling is necessary both for stimulating T_H2 differentiation and for inhibiting T_H1 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 subunit (IL-4R) 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-4R 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-4R that is necessary for T_H2 differentiation. Confocal microscopy showed that TCR stimulation of Dock2^+/+ CD4⁺ T cells resulted in the Rac-dependent internalization of the IL-4R 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-4R would inhibit IL-4-stimulated T_H2 differentiation and thus favor T_H1 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- subunit controlled by the Rac activator Dock2. Nat. Immunol. 8, 1067-1075 (2007). [PubMed]

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