Abstract

Sphingosine 1-phosphate receptor 1 (S1P₁) is a G protein–coupled receptor that is critical for proper lymphocyte development and recirculation. Agonists to S1P₁ are currently in use clinically for the treatment of multiple sclerosis, and these drugs may act on both S1P₁ expressed on lymphocytes and S1P₁ expressed within the central nervous system. Agonists to S1P₁ and deficiency in S1P₁ both cause lymphocyte sequestration in the lymph nodes. In the present study, we show that S1P₁ antagonism induces lymphocyte sequestration in the lymph nodes similar to that observed with S1P₁ agonists while upregulating S1P₁ on lymphocytes and endothelial cells. Additionally, we show that S1P₁ antagonism reverses experimental autoimmune encephalomyelitis in mice without acting on S1P₁ expressed within the central nervous system, demonstrating that lymphocyte sequestration via S1P₁ antagonism is sufficient to alleviate autoimmune pathology.