BACKGROUND: Five different G protein-coupled sphingosine-1-phosphate (S1P) 
receptors (S1P1-S1P5) regulate a variety of physiologic and pathophysiologic 
processes, including lymphocyte circulation, multiple sclerosis (MS), and 
cancer. Although B-lymphocyte circulation plays an important role in these 
processes and is essential for normal immune responses, little is known about 
S1P receptors in human B cells.
OBJECTIVE: To explore their function and signaling, we studied B-cell lines and 
primary B cells from control subjects, patients with leukemia, patients with S1P 
receptor inhibitor-treated MS, and patients with primary immunodeficiencies.
METHODS: S1P receptor expression was analyzed by using multicolor 
immunofluorescence microscopy and quantitative PCR. Transwell assays were used 
to study cell migration. S1P receptor internalization was visualized by means of 
time-lapse imaging with fluorescent S1P receptor fusion proteins expressed by 
using lentiviral gene transfer. B-lymphocyte subsets were characterized by means 
of flow cytometry and immunofluorescence microscopy.
RESULTS: Showing that different B-cell populations express different 
combinations of S1P receptors, we found that S1P1 promotes migration, whereas 
S1P4 modulates and S1P2 inhibits S1P1 signals. Expression of CD69 in activated B 
lymphocytes and B cells from patients with chronic lymphocytic leukemia 
inhibited S1P-induced migration. Studying B-cell lines, normal B lymphocytes, 
and B cells from patients with primary immunodeficiencies, we identified Bruton 
tyrosine kinase, β-arrestin 2, LPS-responsive beige-like anchor protein, 
dedicator of cytokinesis 8, and Wiskott-Aldrich syndrome protein as critical 
signaling components downstream of S1P1.
CONCLUSION: Thus S1P receptor signaling regulates human B-cell circulation and 
might be a factor contributing to the pathology of MS, chronic lymphocytic 
leukemia, and primary immunodeficiencies.