Adaptive immunity depends on mature thymocytes leaving the thymus to enter the bloodstream and the trafficking of T cells through lymphoid organs. Both of these require heterotrimeric Gαi protein signaling, whose intensity and duration are controlled by the regulator of G protein signaling (RGS) proteins. In this study, we show that RGS protein/Gαi2 interactions are essential for normal thymocyte egress, T cell trafficking, and homeostasis. Mature thymocytes with a Gαi2 mutation that disables RGS protein binding accumulated in the perivascular channels of thymic corticomedullary venules. Severe reductions in peripheral naive CD4+ T cells and regulatory T cells occurred. The mutant CD4+ T cells adhered poorly to high endothelial venules and exhibited defects in lymph node entrance and egress. The kinetics of chemokine receptor signaling were disturbed, including chemokine- induced integrin activation. Despite the thymic and lymph node egress defects, sphingosine-1-phosphate signaling was not obviously perturbed. This study reveals how RGS proteins modulate Gαi2 signaling to facilitate thymocyte egress and T cell trafficking.
This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- GTPase-activating protein
- G protein–coupled receptor
- high endothelial venule
- ICAM-1/Fc chimera protein
- perivascular channel
- regulator of G protein signaling
- transendothelial migration
- two-photon laser-scanning microscopy
- Received August 16, 2016.
- Accepted January 24, 2017.