Rac GTPases are involved in development, survival and homeostasis of T cells.

Rac GTPases consist of Rac1, 2 and 3, and each of them have redundant and differential functions. Rac1 is the most ubiquitously and abundantly expressed of the three and has been shown to work as a “molecular switch” in various signal transduction pathways. Although Rac1 and Rac2 are both activated by TCR ligation, little is known about the function of Rac GTPases in the development and activation of T cells. In order to investigate the precise function of Rac GTPases in T cells in vivo, we established dominant negative Rac1 transgenic (dnRac1-Tg) mice controlled by the human CD2 promoter. Total numbers of thymocytes of dnRac1-Tg mice were significantly decreased because of impaired transition from the CD4CD8 double negative stage to the CD4CD8 double positive (DP) stage. Although positive selection of CD4 single positive (SP) was not altered, positive selection of CD8-SP was slightly increased. On the contrary, the number of mature CD4-SP and CD8-SP cells in the spleen, mesenteric lymph nodes and peripheral blood was severely decreased in dnRac1-Tg mice. Proliferation of splenic CD4-SP cells upon TCR stimulation in vitro was unaltered, however, homeostatic proliferation of dnRac1-Tg splenic CD4-SP cells in lymphopenic mice was severely reduced. Finally, we found increased spontaneous apoptosis of DP thymocytes and mature T cells in dnRac1-Tg mice, possibly because of reduced phosphorylation of Akt with or without TCR stimulation. Collectively, the current results indicate that Rac GTPases are important in survival of DP thymocytes and mature T cells in vivo by regulating Akt activation.