S1P1 deletion differentially affects TH17 and Regulatory T cells

Sphingosine-1 phosphate receptor 1 (S1P 1 ) is a G-protein coupled receptor critical for the egress of T and B cells out of lymphoid organs. Although S1P 1 agonists (such as fingolimod) are 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 biology, we specifically deleted S1P 1 in Th17 and T reg cells using IL-17A Cre and Foxp3 Cre mice, respectively. Deletion of S1P 1 in Th17 cells conferred resistance to experimental autoimmune encephalomyelitis (EAE) characterized by reduced Th17 cell distribution across peripheral organs and diminished Th17 cell generation. 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 had an activated phenotype and were more prone to apoptosis, thus converted to effector T reg . The comparison of T reg cells obtained from MS patients treated with fingolimod to those treated with other oral drugs confirmed the switch of T reg cells into effector memory phenotype. 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.