Immunoregulatory Effects of Interferon-β in Suppression of Th17 cells

Abstract

To investigate the immunoregulatory effects of interferon (IFN)-β on CD4+ T cells, we examined the response of CD4+ T cells from IFN-β(+/+) and IFN-β(-/-) mice to CD3/CD28 activation and to differentiation to Th17 lineage, analyzing the expression of signaling effectors, cell surface receptors, production of IL-17, and gene expression profiles. We provide evidence of increased phosphorylation of the membrane proximal kinase associated with TCR activation, ZAP-70, in IFN-β(-/-) T cells compared with IFN-β(+/+) T cells. Anti-CD3/anti-CD28 antibody stimulation of whole splenocytes or CD4+ T cells from IFN-β(-/-) mice results in secretion of IL-17A, in contrast to identical stimulation of cells from IFN-β(+/+) mice, which fails to increase IL-17A production. After CD3/CD28 activation, IFN-β(-/-) CD4+ T cells express higher levels of IRF-4, required for Th17 differentiation, and increased expression of CCR6, IL-23R, IL-6R, and CXCR4, compared with activated IFN-β(+/+) T cells. Notably, cell surface expression of IL-6R and IL-23R is significantly higher in the IFN-β(-/-) CD4+ T cells, with an increased number of double-positive CCR6+IL-23R+ and IL-6R+IL-23R+ CD4+ T cells. On polarization to Th17 lineage, CD4+ T cells from IFN-β(-/-) mice exhibit a more Th17-primed transcriptome compared with CD4+ T cells from IFN-β(+/+) mice. Indeed, when CD4+ T cells from IFN-β(+/+) mice are polarized to Th17 lineage in the presence of IFN-β, many Th17-associated genes are down-regulated. Employing a MOG-peptide-induced experimental autoimmune encephalomyelitis model of multiple sclerosis, we identify a greater proportion of Th17 cells in the lymph nodes of IFN-β(-/-) mice compared with IFN-β(+/+) mice, and increased numbers of CD4+ T cells in the central nervous system of IFN-β(-/-) mice, regardless of the stage of disease. Taken together, our data indicate an immunoregulatory role for IFN-β in the suppression of Th17 cells.

IFN-β Therapy Regulates TLR7-Mediated Response in Plasmacytoid Dendritic Cells of Multiple Sclerosis Patients Influencing an Anti-Inflammatory Status

“…Th17 cell differentiation in humans is orchestrated by IL-1b and IL-23, which stimulate, and by IL-10 and IL-27, which inhibit the differentiation of this cell subset (Chen and O'Shea 2008;Volpe and others 2009;Segura and others 2013). Different reports have demonstrated that IFN-b can affect and inhibit at several levels the differentiation of Th17 cells both in the MS mouse model (Pennell and Fish 2014) and in MS patients. In particular, IFN-b therapy downregulated the expression of IL-1b and the p19 subunit of IL-23 in monocyte-derived DCs from MS-affected individuals and concomitantly induces the p28 subunit of IL-27 (Ramgolam and others 2009).…”

Interferon‐β regulates dendritic cell activation and migration in experimental autoimmune encephalomyelitis

“…Female 2D2 mice, 6–12 weeks of age, were killed, their spleens were harvested and CD4 + T cells were positively selected using a CD4 + selection kit (Miltenyi Biotec) as described previously . The resulting CD4 + T cells were labelled with Cell Proliferation Dye 450 (eBioscience, San Diego, CA), at a concentration of 1 μ m , as per the manufacturer's instructions.…”

“…Mice that are IFN‐ β −/− have been used in EAE studies to validate the importance of IFN‐ β treatment in limiting the pathogenesis of the disease and in relapsing–remitting EAE, where there was evidence of increased frequency of relapses . We and others have shown regulatory roles for IFN‐ β in Th17 cell polarization . Treatment with IFN‐ β decreases IL‐17 gene and protein expression in proliferating murine CD4 + cells and prevents the elevation of IL‐17 mRNA in cells from the CNS draining LNs .…”

Effect of interferon-β1b on CXCR4-dependent chemotaxis in T cells from multiple sclerosis patients

“…Regulation of CXCR4 surface expression may be part of the anti-viral activity of type I IFNs. Indeed, a downregulation of CXCR4-mRNA in human PBMC by in vitro exposure to IFN-a and IFN-g has been demonstrated [35], and mice deficient for IFN-b show increased CXCR4 expression on CD4 1 T cells [36]. Therefore, we asked whether altered CXCR4 surface expression could explain the inhibition of CXCL12-mediated T cell migration.…”