Vav1 promotes T cell cycle progression by linking TCR/CD28 costimulation to FOXO1 and p27^kip1 expression

Vav proteins play a critical role in T cell activation and proliferation by promoting cytoskeleton reorganization, transcription factor activation, and cytokine production. In this study, we investigated the role of Vav in T cell cycle progression. TCR/CD28-stimulated Vav1^-/- T cells displayed a cell cycle block at the G₀-G₁ stage, which accounted tor their defective proliferation. This defect was associated with impaired TCR/CD28-induced phosphorylation of Akt and the Forkhead family transcription factor, FOXO1. The cytoplasmic localization of FOXO1 and its association with 14-3-3τ were also reduced in Vav1^-/- T cells. Consistent with the important role of FOXO1 in p27^kip1 transcription, stimulated Vav1^-/- T cells falled to down-regulate the expression of p27 ^kip1, explaining their G₀-G₁ arrest. These defects were more pronounced in Vav1/Vav3 double-deficient T cells, suggesting partial redundancy between Vav1 and Vav3. Importantly, IL-2-induced p27 ^kip1 down-regulation and cyclin D3 up-regulation and FOXO1 phosphorylation were similar in Vav1^-/- and wild-type T lymphoblasts, indicating that defective FOXO1 phosphorylation and p27^kip1 and cyclin D3 expression do not result from deficient IL-2 signaling in the absence of Vav1. Thus, Vav1 is a critical regulator of a PI3K/Akt/FOXO1 pathway, which controls T cell cycle progression and proliferation.