title: S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress.
abstract: 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 G alpha i-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 G alpha i-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.
authors.affiliation: Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: Trung H M
authors.initials: TH
authors.lastname: Pham
authors.forename: Takaharu
authors.initials: T
authors.lastname: Okada
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Matloubian
authors.forename: Charles G
authors.initials: CG
authors.lastname: Lo
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D005434:Flow Cytometry; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000276:immunology / Q000378:metabolism*; D007150:Immunohistochemistry; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D054400:Receptors, CCR7 / Q000276:immunology / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D049349:Receptors, Lysosphingolipid; D051960:GTP-Binding Protein alpha Subunit, Gi2