Egress: a receptor‐regulated step in lymphocyte trafficking

Abstract

Blood lymphocyte numbers, which are maintained by recirculation through secondary lymphoid organs, are essential for the efficient development of immune responses. Recirculating populations of B and T lymphocytes are regulated by the sphingosine-1-phosphate (S1P) receptor-dependent control of lymphocyte egress. T-cell egress from thymus into blood, egress from lymph node and Peyer's patch into lymph, and B-cell egress into lymph are rapidly and completely inhibited by agonism of S1P receptors. Mesenteric lymph nodes show log-jamming of lymphocytes subjacent to sinus-lining endothelium. Agonism of S1P receptors produces rapid peripheral blood lymphopenia, which is maintained in the presence of receptor agonist. Effector CD4+ and CD8+ T cells, produced by clonal expansion in draining lymph node in response to antigen, are sequestered in lymph node and fail to reach the peripheral blood. The S1P receptor system may represent an early physiological link between the non-specific inflammatory response and the alteration of lymphocyte traffic through draining lymph nodes. Pharmacological subversion of the S1P receptor system, through systemic S1P agonist-induced inhibition of lymphocyte egress, suppresses antigenic responses to peripheral, but not to systemically, delivered antigen. This inhibition induces significant immunosuppression in models of transplantation and autoimmune tissue damage that may prove to be of clinical benefit.

Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate

“…Lymphatic Sinuses-S1P receptor agonists inhibit egress of lymphocytes into lymphatic sinus in peripheral and mesenteric lymph nodes and Peyer's patch but not spleen (7,9). Effects are easily seen histologically within 6 -15 h of a single dose of agonist.…”

“…It regulates heart rate (2), coronary artery blood flow (3), blood pressure (4), endothelial integrity in lung (5,6) and most recently has been shown to regulate the recirculation of lymphocytes (7)(8)(9)(10)(11). Many of the physiologically relevant functions occur in the low nanomolar range, including activation of endothelial nitric oxide synthase (12,13), vasorelaxation (14), and inhibition of thymic egress and lymphocyte recirculation (11).…”

“…S1P receptor function in the immune system has experimental advantages in approaching selective S1P receptor function at vascular interfaces. The maintenance of efficient immune responses depends upon maximizing the probabilities of T lymphocytes encountering their cognate antigens (7). The dispersed anatomy of the immune system requires recirculation of naive lymphocytes, which emerge from their organs of primary lymphopoiesis (thymus and bone marrow), traversing the blood, entering secondary lymphoid organs across high endothelium, and finally crossing sinus-lining endothelium to return to the blood stream via lymph and thoracic duct (19 -22).…”

The Apoptotic Pathway Contributing to the Deletion of Naive CD8 T Cells during the Induction of Peripheral Tolerance to a Cross-Presented Self-Antigen

“…The ability of donor Bcl-2 clone 4 T cells to infiltrate the pancreatic islets led us to question whether the accumulation of Bcl-2 clone 4 T cells was due to increased islet damage and thus, the increased availability of Ag, or other factors such as the inhibition of apoptosis or increased cytokine production. To prevent the initiation of Bcl-2 clone 4 T cell-mediated islet damage, InsHA recipient mice were first treated with an S1P receptor-1 agonist drug (FTY720) that has been shown to prevent lymphocyte egress from the LNs (33,34,36). Treatment with FTY720 had no effect on the activation, proliferation, or accumulation of Bcl-2 clone 4 T cells (Fig.…”

“…The sphingosine-1-phosphate receptor-1 agonist (FTY720) was generously provided by Dr. Hugh Rosen (The Scripps Research Institute) (33)(34)(35)(36) To measure CD8 T cell apoptosis in vivo, single-cell suspensions were prepared from the peripheral and pancreatic LN and Annexin V staining was measured by flow cytometry using Annexin V-allophycocyanin staining Ab (BD Biosciences) according to the manufacturer's instructions. Briefly, cells were stained with Pacific Blue-conjugated anti-CD8 mAb (Caltag Laboratories) and PE-conjugated anti-Thy1.1 mAb (BD Pharmingen) followed by washing twice with cold PBS and then re-suspended in 1ϫ binding buffer at a concentration of 1 ϫ 10 6 cells/tube.…”