Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit

Sphingosine-1-phosphate receptor 1 (S1P₁) was recently shown to be required for lymphocyte egress from lymphoid organs. Here we have examined the relationship between S1P₁ abundance on the cell and egress efficiency. Using an integrin neutralization approach to separate the processes of entry and exit, we show that pertussis toxin treatment reduces lymphocyte egress from lymph nodes. Retrovirally mediated S1P₁ overexpression is sufficient to reduce B cell accumulation in the splenic white pulp and to promote egress of activated T cells from lymph nodes, whereas S1P^+/₁⁻cells have reduced lymph node exit efficiency. Furthermore, lymphocyte S1P₁ is down-regulated in the blood, up-regulated in lymphoid organs, and down-regulated again in the lymph. We propose that cyclical ligand-induced modulation of S1P₁ on circulating lymphocytes contributes to establishing their lymphoid organ transit time.