While much research focuses on T and B cells entering lymphoid organs, Jason Cyster says he's more curious about how they get out. He and colleagues at the University of California San Francisco found a clue to lymphocyte escape, both from the thymus and secondary lymphoid organs, in an immunosuppressant drug, FTY720. The drug sequesters T and B cells in lymphoid organs and is known to interact with sphingosine-1-phosphate (S1P) receptors.
Cyster's team found that in knockout mice lacking S1P receptor 1 (S1P1), mature T cells can't exit the thymus and B cells recirculate poorly.1 While S1P1 is downregulated during normal T-cell maturation and sequestration in lymphoid organs, they found, responsiveness to the receptor is upregulated prior to egress. Lymphocytes require the receptor to recirculate in the periphery and demonstrate a chemotactic response to S1P, which is found in high levels in the blood.
It was surprising to find lymphocytes responding "to a circulatory lipid, rather than protein cues," says Cyster. Jonathan Bromberg at the Mount Sinai School of Medicine in New York City says the paper showed for the first time that chemokines weren't the only signaling molecules important in immune cell trafficking. Five to ten years ago, he adds, lymphocyte egress was believed to be fairly passive. "Now, it turns out, to get out of the lymphoid organs you also need specific signals."