Abstract
BackgroundGrowing evidence emphasizes the relevance of sphingolipids for metabolism and immunity of antigen-presenting cells (APC). APCs are key players in balancing tolerogenic and encephalitogenic responses in immunology. In contrast to the well-known prominent effects of sphingosine-1-phosphate (S1P) on lymphocyte trafficking, modulatory effects on APCs have not been fully characterized.MethodsFrequencies and activation profiles of dendritic cell (DC) subtypes, monocytes, and T cell subsets in 35 multiple sclerosis (MS) patients were evaluated prior and after undergoing fingolimod treatment for up to 24 months. Impact of fingolimod and S1P on maturation and activation profile, pro-inflammatory cytokine release, and phagocytotic capacity was assessed in vitro and ex vivo. Modulation of DC-dependent programming of naïve CD4+ T cells, as well as CD4+ and CD8+ T cell proliferation, was also investigated in vitro and ex vivo.ResultsFingolimod increased peripheral slanDC count—CD1+ DC, and monocyte frequencies remained stable. While CD4+ T cell count decreased, ratio of Treg/Th17 significantly increased in fingolimod-treated patients over time. CD83, CD150, and HLADR were all inhibited, but CD86 was upregulated in DCs after incubation in the presence of fingolimod. Fingolimod but not S1P was associated with reduced release of pro-inflammatory cytokines from DCs and monocytes in vitro and ex vivo. Fingolimod also inhibited phagocytic capacity of slanDCs and monocytes. After fingolimod, slanDCs demonstrated reduced potential to induce interferon–gamma-expressing Th1 or IL-17-expressing Th17 cells and DC-dependent T cell proliferation in vitro and in fingolimod-treated patients.ConclusionsWe present the first evidence that S1P-directed therapies can act additionally as immunomodulators that decrease the pro-inflammatory capabilities of APCs, which is a crucial element in DC-dependent T cell activation and programming.
Highlights
Growing evidence emphasizes the relevance of sphingolipids for metabolism and immunity of antigen-presenting cells (APC)
While CD4+ T cell levels significantly decreased from the start of treatment on (Fig. 1a (G)), there was a gradual reduction of the proportion of CD154+ IL17+ Th17 cells over time
All dendritic cells (DC) subsets showed an increase of CD86 (Fig. 1b (C/G)), which remained unchanged in monocytes (Fig. 1b (L))
Summary
Growing evidence emphasizes the relevance of sphingolipids for metabolism and immunity of antigen-presenting cells (APC). APCs are key players in balancing tolerogenic and encephalitogenic responses in immunology. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is mediated mainly by activated pro-inflammatory CD4+ T helper (Th) cells and cytotoxic CD8+ T cells [1, 2]. Growing evidence is available that suggest a role for antigen-presenting cells (APC) in the pathogenesis of MS via their extraordinary capacity for inducing and expanding pro-inflammatory T cell populations [3, 4]. Dendritic cells (DC) play a crucial role in regulating the balance between encephalitogenic and tolerogenic immunity in MS [5]. Future treatments should include targeted modulation of selective DC and APC functions [8, 9]
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