However, the relative contribution of the Vav1 GEF activity to its function in T cell activation in a disease setting has not been addressed. By using knock-in mice carrying a GEF-inactivating mutation in the Vav1 gene, we demonstrate that Vav1 GEF activity is essential for full T cell activation and proliferation by

allogeneic stimulation. Disruption of only the GEF activity of Vav1, while leaving the adapter functions intact, leads to significantly prolonged allograft survival in a heart transplantation Trichostatin A model. Our findings reveal a strong contribution of Vav1 GEF activity to allogeneic T cell activation, indicating that disruption of Vav1 GEF activity by therapeutic agents may be a novel way to induce immunosuppression. Vav1 has been shown to participate

in the activation of many signal transduction pathways downstream of the TCR, but which of these requires Vav1 GEF activity could only recently be addressed in primary cells [20]. It could be shown that some pathways such as TCR-induced Ca2+ flux and ERK activation are GEF-independent, whereas Omipalisib datasheet activation of others like the PI3K pathway requires Vav1 GEF activity. Still, T cell proliferation and activation after TCR stimulation are severely suppressed when Vav1 GEF activity is disrupted (Fig. 1) [20]. Only at very high concentrations of stimulating CD3 antibody and in the presence of costimulation by CD28, the requirement for Vav1 GEF activity is bypassed. Interestingly, proliferation and activation of T cells

from Vav1AA/AA mice are reduced to the same extent as of T cells from Vav1−/− mice, indicating that Vav1 GEF activity is essential for this Roflumilast response [20]. A similar effect could be observed when T cells were stimulated by allogeneic splenocytes in a mixed lymphocyte reaction, where T cells derived from Vav1AA/AA mice showed a strongly reduced proliferation almost as strong as T cells completely lacking Vav1 (Fig. 2). This is surprising, as T cells from Vav1AA/AA mice have intact Ca2+ and ERK signaling, which is impaired in Vav1−/− T cells [10] and [11]. However, one reason may be that the defects observed in Vav1−/− T cells are only partial. Deficiency of all three Vav family members completely abolishes these signaling events, suggesting a redundant function for the other Vav proteins which could partially compensate Vav1 deficiency [26]. In addition, Vav1 has been shown to promote cell cycle progression via the PI3K pathway, which is defective in both T cells from Vav1−/− and Vav1AA/AA mice [20] and [27]. Furthermore, an important step in T cell activation, especially in the context of allogeneic stimulation, is the formation of the antigen presenting cell (APC)-T cell conjugate and downstream actin polymerization events. Vav1 transduces signals necessary for the activation of integrins important for APC–T cell conjugate formation, a function dependent on the GEF activity of Vav1 [12], [13] and [20].