Sphingosine 1-phosphate (S1P) is essential for lymphocyte egress from lymph node (LN). Despite its importance, it remains unclear how synthesis and secretion of S1P are regulated in LN. Here we report that α9 integrin is expressed on lymphatic endothelial cells (LEC) of medullary sinus in draining LN (dLN). In addition, Tenascin-C (TN-C), one of the α9 integrin ligands, was co-localized with LEC. The stimulation of LEC by TN-C in vitro led to the enhanced secretion of S1P. This α9 integrin-mediated enhancement of S1P secretion was not due to the augmentation of S1P synthesis, but rather induction of S1P transporter, Spns2. Abrogation of α9 integrin-mediated signaling by blocking anti-α9 integrin antibody (55A2C) in vivo resulted in the inhibition of lymphocyte egress from dLN under inflamed condition. Importantly, treatment of 55A2C did not affect lymphocyte egress under naive condition, indicating that blocking of α9 integrin-mediated signaling does not affect lymphocytes egress under non-inflammed condition. Consistent with those data, 55A2C attenuated severity of experimental autoimmune encephalomyelitis (EAE) with concomitantly accumulation of CD4+ T cell in dLN. Thus we propose that lymphocyte egress is regulated by α9 integrin-mediated signaling on LEC via inducing secretion of S1P from LEC under inflamed condition and that manipulation of α9 integrin-mediated signaling can be a potential therapeutic means for various inflammatory disorders.
- Copyright © 2011 by The American Association of Immunologists, Inc.