S1P₁ deletion differentially affects TH17 and Regulatory T cells

Sphingosine-1 phosphate receptor 1 (S1P₁) is critical for the egress of T and B cells out of lymphoid organs. Although S1P₁ agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P₁ signaling regulates Th17 and T_reg cell homeostasis. To study the impact of S1P₁ signaling on Th17 and T_reg cell biology, we specifically deleted S1P₁ in Th17 and T_reg cells using IL-17A ^Cre and Foxp3 ^Cre mice, respectively. Deletion of S1P₁ in Th17 cells conferred resistance to experimental autoimmune encephalomyelitis (EAE). On the other hand, permanent deletion of S1P₁ in T_reg cells resulted in autoimmunity and acute deletion rendered mice more susceptible to EAE. Importantly, our study revealed that S1P₁ not only regulated the egress of T_reg cells out of lymphoid organs and subsequent non-lymphoid tissue distribution but also their phenotypic diversity. Most of the T_reg cells found in S1P₁-deficient mice as well as MS patients on fingolimod therapy had an activated phenotype and were more prone to apoptosis, thus converted to effector T_reg. Our results provide novel insight into the functions of S1P₁ and potential impact of long term fingolimod use on Th17 and T_reg cell biology and general health in MS patients.