Figure 6.

Summary model relating requirements for lymph node egress and possible effect of cyclical S1P₁ expression on lymphocyte recirculation. Lymphocytes in the blood, which has abundant extracellular S1P, have little surface S1P₁. After migration into a lymphoid organ in an integrin- and Gαi-dependent manner, the cells begin to up-regulate S1P₁, perhaps because extracellular S1P concentrations are no longer adequate to cause receptor down-modulation. Only when S1P₁ is up-regulated do the cells become fully egress competent and the time required for up-regulation may help ensure that the cells dwell in the tissue for a period of hours. Additional undefined factors are also anticipated to influence lymphoid organ transit time. Egress occurs in a manner that does not require α4 and β2 integrins but Gαi contributes to this process, perhaps acting downstream of S1P₁. Exit sites are suggested to have high S1P levels, and S1P₁ signaling is essential for egress to occur. By down-modulating S1P₁, FTY720 can block the egress step. Once in the lymph, S1P₁ is down-regulated, most likely due to the abundance of S1P, and the cycle begins again. Transit through the splenic white pulp is suggested to involve a similar cycle of events except that egress is into the blood. The reduced S1P₁ levels on circulating lymphocytes may also help ensure that S1P does not antagonize chemokine signaling required for lymphoid organ entry.