Zhang, L., Yuan, S., Cheng, G. & Guo, B. Type I IFN promotes IL-10 production from T cells to suppress Th17 cells and Th17-associated autoimmune inflammation. PLoS One 6, e28432

McMaster University, Canada
PLoS ONE (Impact Factor: 3.23). 12/2011; 6(12):e28432. DOI: 10.1371/journal.pone.0028432
Source: PubMed


Whereas the immune system is essential for host defense against pathogen infection or endogenous danger signals, dysregulated innate and adaptive immune cells may facilitate harmful inflammatory or autoimmune responses. In the CNS, chronic inflammation plays an important role in the pathogenesis of neurodegenerative diseases such as multiple sclerosis (MS). Our previous study has demonstrated a critical role for the type I IFN induction and signaling pathways in constraining Th17-mediated experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. However, it remains unknown if self-reactive Th17 cells can be reprogrammed to have less encephalitogenic activities or even have regulatory effects through modulation of innate pathways. In this study, we investigated the direct effects of type I IFN on Th17 cells. Our data show that IFNβ treatment of T cells cultured under Th17 polarizing conditions resulted in reduced production of IL-17, but increased production of IL-10. We also found that IFNβ induced IL-10 production by antigen specific T cells derived from immunized mice. Furthermore, IFNβ treatment could suppress the encephalitogenic activity of myelin-specific T cells, and ameliorate clinical symptoms of EAE in an adoptive transfer model. Together, results from this study suggest that IFNβ may induce antigen-specific T cells to produce IL-10, which in turn negatively regulate Th17-mediate inflammatory and autoimmune response.

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Available from: Shunzong Yuan, Mar 21, 2015
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    • "IFN-β is a cytokine that works by increasing anti-inflammatory cytokines (Guo, Chang and Cheng, 2008; Ramgolam et al., 2009; Zhang et al., 2011) and reducing pro-inflammatory cytokines (Kozovska et al., 1999; Ozenci et al., 1999; Liu et al., 2001). It has been shown to reduce relapse rates and prolong time between relapses in RRMS (Paty and Li, 1993; The IFNB Multiple Sclerosis Study, 1993) and can delay the time of conversion from clinically isolated syndrome (CIS) to clinical MS vs. placebo (Jacobs et al., 2000; Kappos et al., 2006; Comi et al., 2012). "
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    ABSTRACT: Multiple sclerosis is a chronic demyelinating autoimmune disease with uncertain aetiology. Due to the heterogeneity of the disease, patients may present with a wide variety of neurological symptoms such as optic neuritis, sensory deficits or cerebellar dysfunction. It remains a disease showing little hope in terms of finding a cure. Although current therapies, such as interferon-β and glatiramer acetate, provide symptomatic relief and can delay the degenerative process, there is still a large impact on quality of life as these therapies lack an ability to reverse damage occurring prior to treatment. Recently, cell therapy has emerged as a promising treatment with signs of recovery both pathologically and clinically in a variety of animal models. Given the multifaceted capabilities of the various stem cells, including immunomodulation and neuroprotection, their potential use as a comprehensive therapy is much more promising than any pharmacological therapy to date. Here, the latest advances of cell therapy are discussed, in terms of potential efficacy, the various cell types that are used, their mechanisms of action and the obstacles that still need to be overcome for translation into a clinical setting.
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    • "It is likely that IFN-Is up-regulate PD-1 expression (e.g., on regulatory T cells) and PD-L1 (e.g., on DCs) on cells resulting in a milieu where PD-1/PD-L1 interactions occur; this could facilitate IL-10 production and exhaustion of T cell function during chronic viral infections (19, 76–80). A caveat here is that IFN-Is in some instances can also inhibit IL-10 production and IL-10 production can occur independently of IFN-I signaling (76, 81). Furthermore, IFN-Is up-regulate pro-apoptotic molecules such as Bak on T cells to induce apoptosis independently of T cell exhaustion (82). "
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    ABSTRACT: It has been well-established that type I interferons (IFN-Is) have pleiotropic effects and play an early central role in the control of many acute viral infections. However, their pleiotropic effects are not always beneficial to the host and in fact several reports suggest that the induction of IFN-Is exacerbate disease outcomes against some bacterial and chronic viral infections. In this brief review, we probe into this mystery and try to develop answers based on past and recent studies evaluating the roles of IFN-Is in infection and immunity as this is vital for developing effective IFN-Is based therapeutics and vaccines. We also discuss the biological roles of an emerging IFN-I, namely IFN-ε, and discuss its potential use as a mucosal therapeutic and/or vaccine adjuvant. Overall, we anticipate the discussions generated in this review will provide new insights for better exploiting the biological functions of IFN-Is in developing efficacious therapeutics and vaccines in the future.
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    • "CD4 + T cells were collected from draining lymph nodes by positive selection, and the cytokines produced from MOG-reactive CD4 + T cells following restimulation with MOG 35–55 were examined. IFN-β treatment alone suppressed IFN-γ and IL-17 production (Fig. 1A and B), as described previously (Guo et al., 2008; Zhang et al., 2011). Sema4A alone did not change the production of IFN-γ and IL-17. "
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    ABSTRACT: Approximately one-third of patients with multiple sclerosis (MS) respond poorly to interferon-beta (IFN-β) therapy. Serum Sema4A is increased in MS patients, and those who have high Sema4A do not respond to IFN-β therapy. In this study, we investigated whether recombinant Sema4A abrogates the efficacy of IFN-β in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Administration of Sema4A concurrently with IFN-β diminished the efficacy of IFN-β in EAE. These effects of Sema4A were attributed to promote Th1 and Th17 differentiation and to increase adhesive activation of T cells to endothelial cells, even in the presence of IFN-β.
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