Promotion of Lymphocyte Egress into Blood and Lymph by Distinct Sources of Sphingosine-1-Phosphate

TLDR

Lymphocytes require sphingosine‑1‑phosphate (S1P) receptor‑1 to exit lymphoid organs, but the source(s) of extracellular S1P and whether S1P directly promotes egress are unknown. By conditionally ablating the two kinases that generate S1P in mice, the study shows that plasma S1P is mainly hematopoietic, with erythrocytes as a major contributor, whereas lymph S1P originates from a distinct radiation‑resistant source. Kinase‑deficient mice exhibited markedly reduced lymphocyte egress from thymus and secondary lymphoid organs; restoring plasma S1P rescued blood egress but not lymph, requiring lymphocyte S1P‑R1, demonstrating that separate plasma and lymph S1P sources drive exit and that disrupting compartmentalized S1P signaling underlies S1P‑R1 agonist immunosuppression.

Abstract

Lymphocytes require sphingosine-1-phosphate (S1P) receptor-1 to exit lymphoid organs, but the source(s) of extracellular S1P and whether S1P directly promotes egress are unknown. By using mice in which the two kinases that generate S1P were conditionally ablated, we find that plasma S1P is mainly hematopoietic in origin, with erythrocytes a major contributor, whereas lymph S1P is from a distinct radiation-resistant source. Lymphocyte egress from thymus and secondary lymphoid organs was markedly reduced in kinase-deficient mice. Restoration of S1P to plasma rescued egress to blood but not lymph, and the rescue required lymphocyte expression of S1P-receptor-1. Thus, separate sources provide S1P to plasma and lymph to help lymphocytes exit the low-S1P environment of lymphoid organs. Disruption of compartmentalized S1P signaling is a plausible mechanism by which S1P-receptor-1 agonists function as immunosuppressives.