The S1P-analog FTY720 differentially modulates T-cell homing via HEV:: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches

Sphingosine-1-phosphate (S1P) and its receptor S1P, control T-cell egress from thymus and secondary lymphoid organs (SLOs). To further define the role of S1P, in lymphocyte trafficking, we performed adoptive transfer experiments and intravital microscopy (IVM) using both S1P(1)(-/-) lymphocytes and recipient wild-type (WT) mice treated with FTY720, an immunosuppressant that downmodulates S1P receptors. S1P, deficiency and FTY720 caused rapid disappearance of T cells from blood, prolonged retention in SLOs, and accumulation in bone marrow, but did not alter interstitial T-cell motility in peripheral lymph nodes (PLNs) as assessed by multiphoton IVM. However, S1P(1)(-/-) lymphocytes displayed reduced short-term homing to PLNs due to attenuated integrin-mediated firm arrest in high endothelial venules (HEVs). By contrast, S1P(1)(-/-) T cells homed normally to Peyer patches (PPs), whereas S1P(1)(-/-) B cells had a marked defect in homing to PPs and arrested poorly in PP HEVs. Therefore, S1P, not only controls lymphocyte egress from SLOs, but also facilitates in a tissue- and subset-specific fashion integrin activation during homing. Interestingly, FTY720 treatment enhanced accumulation of both S1P(1) sufficient and S1P(1)(-/-) T cells in PPs by enhancing integrin-mediated arrest in HEVs. Thus, FTY720 exerts unique effects on T-cell traffic in PPs that are independent of T-cell-expressed S1P(1).