S1P1 Receptor Signaling Overrides Retention Mediated by G[alpha]i-Coupled Receptors to Promote T Cell Egress

• Published in: Immunity (Cambridge, Mass.) Vol. 28; no. 1; p. 122
• Main Authors: Pham, Trung HM, Okada, Takaharu, Matloubian, Mehrdad, Lo, Charles G, Cyster, Jason G
• Format: Journal Article
• Language: English
• Published: Cambridge Elsevier Limited 18-01-2008
• Subjects: Cloning; Colleges & universities; Flow cytometry; Ligands; Lymphatic system; Lymphocytes; Retention; Rodents
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2007.11.017

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 S1P1expression and was antagonized by CCR7. These findings suggest a model where S1P1acts in the lymphocyte to promote lymph node egress by overcoming retention signals mediated by CCR7 and additional Gαi-coupled receptors. Furthermore, by simultaneously upregulating S1P1and downregulating CCR7, T cells that have divided multiple times switch to a state favoring egress over retention.