Abstract
Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by persistent inflammation orchestrated by cluster of differentiation (CD) 4 T helper (Th) cells. In particular, Th1 and Th17 cells amplify, whereas T regulatory (Treg) cells moderate inflammation. The role of other Th subsets in MS is not clear. In the present study, we investigated the generation of different Th responses by human dendritic cells (DCs) in MS. We compared the production of several Th cytokines by naive CD4+ T-cells polarized with myeloid and plasmacytoid DCs (mDCs and pDCs) in healthy donors (HD) and relapsing-remitting (RR)-MS patients. We found that resiquimod-stimulated mDCs were able to activate Th17 differentiation, whereas pDCs induced interleukin (IL)-10-producing Th cells. Surprisingly, resiquimod-stimulated pDCs from MS patients also significantly induced the differentiation of Th9 cells, which produce IL-9 and are known to be involved in allergic diseases. We investigated the potential role of IL-9 in MS. We found that IL-9 activated signal transducer and activator of transcription (STAT) 1 and STAT5 phosphorylation and interfered with IL-17 and interferon (IFN) regulatory transcription factor (IRF)-4 expression in Th17-polarized cells. Moreover, in the cerebrospinal fluid (CSF) of 107 RR-MS patients, IL-9 inversely correlated with indexes of inflammatory activity, neurodegeneration and disability progression of MS. High levels of IL-9 were associated with the absence of IL-17 in the CSF of RR-MS patients. Our results demonstrate a Th9-inducing potential of pDCs in MS, suggesting an immunoregulatory role leading to attenuation of the exaggerated Th17 inflammatory response.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS)
Plasmacytoid dendritic cells from RR-MS patients induce Th9 polarization Given the crucial role of DCs in polarizing T helper (Th) responses, we hypothesized a differential role of DCs obtained from MS patients compared with DCs from healthy donors (HD) in driving Th differentiation
Naive CD4+ T-cells from HD and RR-MS patients were co-cultured with autologous plasmacytoid dendritic cell (pDC) or myeloid dendritic cell (mDC) stimulated with resiquimod (R-848), an agonist for Toll-like receptor (TLR) 7 expressed by pDCs and for TLR8 expressed by mDCs (Table 1)
Summary
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). In the past 10 years, three additional Th cell subtypes have been discovered and designated Th17, Th9 and Th22 cells, according to the signature cytokine secreted by Abbreviations: ARR, annualized relapse rate; CD, cluster of differentiation; CNS, central nervous system; CSF, cerebrospinal fluid; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; EDSS, expanded disability status scale; HD, healthy donor(s); H-IL9, high IL-9; i.v., intravenously; IFN, interferon; IL, interleukin; IL-9R, IL-9 receptor; IRF, interferon regulatory transcription factor; L-IL9, low IL-9; mDC, myeloid dendritic cell; MS, multiple sclerosis; MSSS, MS severity scale; MV, macular volume; NfL, neurofilament light chain; OCT, optical coherence tomography; OR, odds ratio; PBMC, peripheral blood mononuclear cell; pDC, plasmacytoid dendritic cell; PI, progression index; RNFL, nerve fibre layer; ROR, retinoic acid-related orphan receptor; RR, relapsing–remitting; RT, reverse transcription; SE, standard error; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; Th, T helper; TLR, Toll-like receptor; TNF, tumour necrosis factor; Treg, T regulatory
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