T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple sclerosis

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.

Neutralization of interleukin‐9 ameliorates experimental stroke by repairing the blood–brain barrierviadown‐regulation of astrocyte‐derived vascular endothelial growth factor‐A

“…IL-9 blockade in EAE may also be mediated by inhibiting the proliferation and differentiation of MOG-specific T cells (41). However, some scholars have obtained discrepant results, showing that plasma-like dendritic cells in patients with relapsed MS have the ability to induce Th9 cell differentiation, which can reduce the immune response of Th17 cells through the STAT1/STAT5 pathway (42). Aside from IL-9, other inflammatory factors reported in the literature include IL-1b, IL-6, and TNF-a, which can affect the integrity of the BBB and expression of TJPs in the brain (43)(44)(45).…”

TGF‐β regulation of encephalitogenic and regulatory T cells in multiple sclerosis

“…A pathogenic role for Th9 cells was a surprising outcome since it had previously been shown that IL‐9 has a regulatory function . Another recent study showed that IL‐9 negatively regulates Th17 cells . In addition, IL‐9 levels in the CSF of MS patients were shown to negatively correlate with inflammation, neurodegeneration, and disease progression , supporting a regulatory role for IL‐9 in MS. An in vitro study showed that IL‐9 in the presence of IFN‐γ promotes the proliferation of oligodendrocyte precursor cells, whereas IL‐9 in the presence of IL‐17 inhibits oligodendrocyte precursor cell proliferation, suggesting that Th9 cells may have inverse functions in the presence of Th1 or Th17 cells .…”

Frequency of Th9 Cells in Different Stages of Rheumatoid Arthritis

“…In addition, the mean percentage of Th9 in established RA patients was not significantly different from that in VERA patients (P>0.05). There was no statistically significant difference in the mean percentage of circulating Th9 cells between RA patients with DAS-28 of >3.2 (1.47 ± 0.58%) and those by plasmacytoid dendritic cells could have an immunoregulatory role in the Th17 cellsgenerated inflammation in multiple sclerosis (31). Nonetheless, the exact role of Th9 might rely on the tissue microenvironment and cytokines present in the milieu (32).…”