S1P1 deletion differentially affects TH17 and Regulatory T cells

Sphingosine-1 phosphate receptor 1 (S1P 1 ) is critical for the egress of T and B cells out of lymphoid organs. Although S1P 1 agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P 1 signaling regulates Th17 and T reg cell homeostasis. To study the impact of S1P 1 signaling on Th17 and T reg cell biology, we specifically deleted S1P 1 in Th17 and T reg cells using IL- 1 7A Cre and Foxp3 Cre mice, respectively. Deletion of S1P 1 in Th17 cells conferred resistance to experimental autoimmune encephalomyelitis (EAE). On the other hand, permanent deletion of S1P 1 in T reg cells resulted in autoimmunity and acute deletion rendered mice more susceptible to EAE. Importantly, our study revealed that S1P 1 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 S1P 1 -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 S1P 1 and potential impact of long term fingolimod use on Th17 and T reg cell biology and general health in MS patients.