Abstract
Abstract S1P1 is a G-protein coupled receptor expressed by lymphocytes and is required for their egress out of secondary lymphoid organs. Fingolimod, an agonist of four S1P receptors including S1P1, is used in multiple sclerosis (MS) treatment in humans; however, less is known regarding the impact of S1P1 agonists on the egress-independent biology and functions of human Th17 and Treg cells. In this study, we explored the effects of S1P1 agonists SEW2871 and FTY720 on the ex vivo generation and functions of human Th17 and Treg cells. We report that a selective S1P1 agonist SEW2871 inhibited human Th17 development ex vivo, from naïve T cells, associated with reduced IL-17 and IL-22 production, demonstrated by ELISA and intracellular cytokine staining. On the other hand, Treg generation was augmented in SEW2871+ cultures. Additionally, SEW2871-exposed monocytes and dendritic cells produced less IL-23, a cytokine required for Th17 cell-expansion and pathogenicity. Th17 differentiation in the presence or absence of antigen presenting cells revealed that SEW2871 could inhibit Th17 generation either by blocking APC-derived IL-23 or directly affecting T cells. Our data provide novel information as to egress-independent effects of S1P1 agonists on Th17 cells.
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