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.