Guanine Nucleotide-Binding Proteins of the G12 Family Shape Immune Functions by Controlling CD4+ T Cell Adhesiveness and Motility

SummaryIntegrin-mediated adhesion plays a central role in T cell trafficking and activation. Genetic inactivation of the guanine nucleotide-binding (G) protein α-subunits Gα12 and Gα13 resulted in an increased activity of integrin leukocyte-function-antigen-1 in murine CD4+ T cells. The interaction with allogeneic dendritic cells was enhanced, leading to an abnormal proliferative response in vitro. In vivo, T cell-specific inactivation of Gα12 and Gα13 caused lymphadenopathy due to increased lymph node entry and enhanced T cell proliferation, and the susceptibility toward T cell-mediated diseases was enhanced. Mechanistically, we show that in the absence of Gα12 and Gα13 the activity of the small GTPases Rac1 and Rap1 was increased, whereas signaling of the small GTPase RhoA was strongly reduced. Our data indicate that locally produced mediators signal through Gα12- and Gα13-coupled receptors to negatively regulate cell polarization and adhesiveness, thereby fine-tuning T cell trafficking, proliferation, and susceptibility toward T cell-mediated diseases.