FTY720 blocks egress of T cells in part by abrogation of their adhesion on the lymph node sinus.

ABSTRACT: Egress of lymphocytes from lymphoid tissues is a complex process in which G?i-mediated signals play a decisive role. We show here that although FTY720, an agonist of the sphingosine 1-phosphate (S1P)(1) receptor, induces S1P(1) receptor internalization sufficiently in the presence or absence of G?i2 or G?i3, the drug blocks egress of wild-type (WT) and G?i3-deficent T cells, but not G?i2-deficient T cells, in both WT and G?i2-deficient hosts. Intravital imaging of lymph nodes revealed that all three groups of T cells approached and engaged cortical sinusoids similarly in the presence or absence of FTY720. The cells also entered and departed the sinus at an almost identical frequency in the absence of the drug. However, after engagement of the sinus, most WT and G?i3-deficient T cells retracted and migrated back into the parenchyma in FTY720-treated animals, due to a failure of the cells to establish adhesion on the sinus, whereas G?i2-deficient T cells adhered firmly on the sinus, which prevented their retraction, facilitating their transmigration of the lymphatic endothelial barrier. These data confirm egress of G?i2(-/-) T cells independent of S1P-mediated chemotaxis and failure of FTY720 to close lymphatic stromal channels and argue for the first time, to our knowledge, that FTY720 induces lymphopenia in part by impairing T cell adhesion to the sinus in a manner dependent on G?i2.

SUBMITTER: Zhi L 

PROVIDER: S-EPMC3167479 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature