IL‐10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis

Abstract

T regulatory cells type 1 (Tr1 cells) are excellent candidates for cell therapy in multiple sclerosis (MS). The aim of our study was to assess the functional state of Tr1 cells and IL-10R signaling in patients with MS. Tr1 cells were induced in vitro by activation with anti-CD46 antibodies in controls and patients with MS. Cells were phenotyped by cytometry and suppression assays, and the expression of cytokines and transcription factors was evaluated by real-time PCR, ELISA, cytometry and Western blotting. We found that the activity of Tr1 cells and IL-10R signaling is impaired in MS patients since Tr1 cells isolated from MS patients produced less IL-10 than those obtained from controls. Indeed, the supernatants from Tr1 cells from controls did not suppress the proliferation of stimulated CD4 + cells from patients with MS. Furthermore, the IL-10R signaling pathway was not fully active in CD4 + cells from MS patients and these cells had higher baseline levels of SOCS3 transcripts than controls. Indeed, after in vitro IL-10 stimulation, the expression levels of the STAT1, STAT3 and IL-10RA genes were higher in MS patients than in controls. Moreover, Stat-3 phosphorylation was lower in controls than in patients after IL-10 stimulation. These results indicate that IL-10 regulatory function is impaired in patients with MS.

Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice

“…Indeed, functional screening of peripheral blood lymphocytes from a subgroup of monozygotic twins indicated decreased IL-10 production in MS-derived samples. This is in accord with previous work, which described decreases of Tr1-like, IL-10-producing T cells (30)(31)(32). The differential IL-10 response noted in human PBMCs was mirrored in gnotobiotic RR mice.…”

CD46 Engagement on Human CD4+T Cells Produces T Regulatory Type 1-Like Regulation of Antimycobacterial T Cell Responses

“…Although the exact in vivo induction conditions and functional role(s) of CD46-induced suppressor T cells are currently not possible to create in a small animal model (see introduction), evidence for the physiological significance of the CD46 regulatory signaling pathway in humans is emerging. A recent report by Astier et al established a connection between defects in the CD46-mediated induction of IL-10 in CD4 ϩ T cells with multiple sclerosis (MS), which suggests that CD46 may indeed play a role in the prevention of autoimmunity in humans (3,32). Similarly, dysfunctional CD46-mediated IL-10 production in T cells has now been connected with acute experimental autoimmune encephalomyelitis (EAE) in cynomolgus monkeys (which express CD46 naturally) (30).…”

The challenge of multiple sclerosis: How do we cure a chronic heterogeneous disease?

“…21 Defects in regulatory T-cell function have been described in MS, [22][23][24] and a major goal of MS immunotherapy is to induce regulatory cells in a physiological and nontoxic fashion (see Fig 2). Regulatory T cells can broadly be classified as natural Tregs and induced Tregs.…”