S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress

Immunity. 2008 Jan;28(1):122-33. doi: 10.1016/j.immuni.2007.11.017. Epub 2007 Dec 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Chemotaxis, Leukocyte / immunology*
  • Flow Cytometry
  • GTP-Binding Protein alpha Subunit, Gi2 / immunology
  • GTP-Binding Protein alpha Subunit, Gi2 / metabolism*
  • Immunohistochemistry
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology*
  • Lymph Nodes / metabolism
  • Mice
  • Mice, Transgenic
  • Receptors, CCR7 / immunology
  • Receptors, CCR7 / metabolism
  • Receptors, Lysosphingolipid / immunology
  • Receptors, Lysosphingolipid / metabolism*
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • Ccr7 protein, mouse
  • Receptors, CCR7
  • Receptors, Lysosphingolipid
  • GTP-Binding Protein alpha Subunit, Gi2