Abstract

Sphingosine-1 phosphate receptor 1 (S1PR1) is expressed by lymphocytes and regulates their egress from secondary lymphoid organs. Innate lymphoid cell (ILC) family has been expanded with the discovery of group 1, 2 and 3 ILCs, namely ILC1, ILC2 and ILC3. ILC3 and ILC1 have remarkable similarity to CD4+ helper T cell lineage members Th17 and Th1, respectively, which are important in the pathology of multiple sclerosis (MS). Whether human ILC subsets express S1PR1 or respond to its ligands have not been studied. In this study, we used peripheral blood/cord blood and tonsil lymphocytes as a source of human ILCs. We show that human ILCs express S1PR1 mRNA and protein and migrate toward S1P receptor ligands. Comparison of peripheral blood ILC numbers between fingolimod-receiving and treatment-free MS patients revealed that, in vivo, ILCs respond to fingolimod, an S1PR1 agonist, resulting in ILC-penia in circulation. Similarly, murine ILCs responded to fingolimod by exiting blood and accumulating in the secondary lymph nodes. Importantly, ex vivo exposure of ILC3 and ILC1 to fingolimod or SEW2871, another S1PR1 antagonist, reduced production of ILC3- and ILC1- associated cytokines GM-CSF, IL-22, IL-17, and IFN-γ, respectively. Surprisingly, despite reduced number of lamina propria-resident ILC3s in the long-term fingolimod-treated mice, ILC3-associated IL-22, IL-17A, GM-CSF and antimicrobial peptides were high in the gut compared to controls, suggesting that its long term use may not compromise mucosal barrier function. To our knowledge, this is the first study to investigate the impact of fingolimod on human ILC subsets in vivo and ex vivo, and provides insight into the impact of long term fingolimod use on ILC populations.

Highlights

  • S1P receptor 1 (S1PR1) is a G-protein coupled receptor expressed by endothelial cells and lymphocytes

  • Lineage negative (TCRαβ, TCRγδ, CD34, CD123, CD94, CD14, BDCA2, FcεRIα, CD1a, CD11c, CD19, B220-) CD3-CD161+CD127+cKit+ cells were sorted as ILC3, Lineage-CD3-CD161+CD127+cKit- cells were sorted as ILC1 and Lineage-CD3-CD161+CD127+CRTH2+ cells sorted as ILC2 (Figure 1A)

  • We examined the expression of S1P receptors by real time qPCR in the murine intestinal ILC3 and ILC2/ILC1s

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Summary

Introduction

S1P receptor 1 (S1PR1) is a G-protein coupled receptor expressed by endothelial cells and lymphocytes. Fingolimod (FTY720 or GilenyaTM) is a structural analog of sphingosine-1 that blocks lymphocyte egress into blood or lymph by inducing S1PR1 internalization [9]. Approved for the treatment of MS [11], in some patients, cessation or initiation of fingolimod therapy resulted in exacerbation of MS and formation of tumefactive lesions in the brain [12,13,14,15,16]. Ozanimod and siponimod are more specific than fingolimod and bind S1PR1 and S1PR5. S1PR1 antagonists/agonists are tested for other conditions besides MS, including psoriasis, graft vs host disease (GVHD) and inflammatory bowel diseases (IBD) [17,18,19]. The potential for the broader use of S1PR1 modulators for the treatment of a host of autoimmune conditions underlines the need for a better understanding of S1PR1 functions in various cell types in the body

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