The splenic marginal zone is a site of blood flow, and the specialized B cell population that inhabits this compartment has been linked to the capture and follicular delivery of blood-borne antigens. However, the mechanism of this antigen transport has remained unknown. Here we show that marginal zone B cells were not confined to the marginal zone but continuously shuttled between the marginal zone and follicular areas, such that many of the cells visited a follicle every few hours. Migration to the follicle required the chemokine receptor CXCR5, whereas return to the marginal zone was promoted by the sphingosine 1-phosphate receptors S1P1 and S1P3. Treatment with an S1P1 antagonist caused displacement of marginal zone B cells from the marginal zone. Marginal zone-follicle shuttling of marginal zone B cells provides an efficient mechanism for systemic antigen capture and delivery to follicular dendritic cells.
T cell egress from the thymus is essential for adaptive immunity, yet the requirements for and sites of egress are incompletely understood. We have shown that transgenic expression of sphingosine-1-phosphate receptor-1 (S1P1) in immature thymocytes leads to their perivascular accumulation and premature release into circulation. Using an intravascular procedure to label emigrating cells, we found that mature thymocytes exit via blood vessels at the corticomedullary junction. By deleting sphingosine kinases in neural crest-derived pericytes, we provide evidence that these specialized vessel-ensheathing cells contribute to the S1P that promotes thymic egress. Lymphatic endothelial cell-derived S1P was not required. These studies identify the major thymic egress route and suggest a role for pericytes in promoting reverse transmigration of cells across blood vessel endothelium.
Dengue fever is a mosquito-borne viral disease of global importance with no available antiviral therapy. We assessed the ability of mycophenolic acid (MPA), a drug currently used as an immunosuppressive agent, to inhibit dengue virus (DV) antigen expression, RNA replication, and virus production. Pharmacological concentrations of MPA effectively blocked DV infection, decreasing the percentage of infected cells by 99% and the levels of secreted virus by up to a millionfold. Results were reproduced with four hepatoma cell lines and different flaviviruses, including a recent West Nile virus isolate. Experiments were performed to define the stage in the viral lifecycle at which MPA abrogates infection. Early steps in viral infection, such as viral entry and nucleocapsid uncoating, were not the primary targets of MPA action since its inhibitory effect was retained when naked DV RNA was transfected directly into cells. Biosynthetic labeling experiments showed that MPA did not block the initial phase of viral translation but did interfere with viral protein synthesis in the amplification phase. Quantitative RT-PCR demonstrated that MPA prevented the accumulation of viral positive- and negative-strand RNA as the infection proceeded. We conclude that MPA inhibits flavivirus infection by preventing synthesis and accumulation of viral RNA.
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