S1P1 receptor signaling overrides retention mediated by Gαi-coupled receptors to promote T cell egress

The mechanism by which sphingosine-1-phosphate receptor-1 (S1P(1)) acts to promote lymphocyte egress from lymphoid organs is not defined. Here, we showed that CCR7-deficient T cells left lymph nodes more rapidly than wild-type cells did, whereas CCR7-overexpressing cells were retained for longer. After treatment with FTY720, an agonist that causes down-modulation of lymphocyte S1P(1), CCR7-deficient T cells were less effectively retained than wild-type T cells. Moreover, treatment with pertussis toxin to inactivate signaling via G alpha(i)-protein-coupled receptors restored egress competence to S1P(1)-deficient lymphocytes. We also found that T cell accumulation in lymph node cortical sinusoids required intrinsic S1P(1) expression and was antagonized by CCR7. These findings suggest a model where S1P(1) acts in the lymphocyte to promote lymph node egress by overcoming retention signals mediated by CCR7 and additional G alpha(i)-coupled receptors. Furthermore, by simultaneously upregulating S1P(1) and downregulating CCR7, T cells that have divided multiple times switch to a state favoring egress over retention.