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

THM Pham, T Okada, M Matloubian, CG Lo, JG Cyster - Immunity, 2008 - cell.com
THM Pham, T Okada, M Matloubian, CG Lo, JG Cyster
Immunity, 2008cell.com
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 downmodulation of lymphocyte S1P 1, CCR7-deficient T cells were less effectively
retained than wild-type T cells. Moreover, treatment with pertussis toxin to inactivate …
Summary
The mechanism by which sphingosine-1-phosphate receptor-1 (S1P1) 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 downmodulation of lymphocyte S1P1, CCR7-deficient T cells were less effectively retained than wild-type T cells. Moreover, treatment with pertussis toxin to inactivate signaling via Gαi-protein-coupled receptors restored egress competence to S1P1-deficient lymphocytes. We also found that T cell accumulation in lymph node cortical sinusoids required intrinsic S1P1 expression and was antagonized by CCR7. These findings suggest a model where S1P1 acts in the lymphocyte to promote lymph node egress by overcoming retention signals mediated by CCR7 and additional Gαi-coupled receptors. Furthermore, by simultaneously upregulating S1P1 and downregulating CCR7, T cells that have divided multiple times switch to a state favoring egress over retention.
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