Interferon-ß regulates dendritic cell activation and migration in experimental autoimmune encephalomyelitis.

CD11c+ dendritic cells (DCs) exert a critical role as antigen-presenting cells in regulating pathogenic T cells in multiple sclerosis (MS). To determine whether the therapeutic benefit of interferon-ß (IFN-ß) treatment for MS is in part influenced by IFN regulation of DC function, we examined the immunophenotype of DCs derived from IFN-ß+/+ and IFN-ß-/- mice using a myelin oligodendrocyte glycoprotein (MOG) peptide-induced mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Our earlier work identified that IFN-ß-/- mice exhibit earlier onset and more rapid progression of neurological impairment compared with IFN-ß+/+ mice. In this study we show that lipopolysaccharide-/MOG peptide-stimulated IFN-ß-/- DCs secrete cytokines associated with pathological T helper type 17 rather than regulatory T-cell polarization and exhibit increased CD80 and MHCII expression when compared with stimulated IFN-ß+/+ DCs. IFN-ß-/- DCs from mice immunized to develop EAE induce greater proliferation of MOG-transgenic CD4+ T cells and promote interleukin-17 production by these T cells. Adoptive transfer of MOG peptide-primed IFN-ß-/- DCs into IFN-ß+/+ and IFN-ß-/- mice immunized to develop EAE resulted in their rapid migration into the central nervous system of recipient mice, before onset of disease, which we attribute to failed signal transducer and activator of transcription 1-mediated inhibition of CCR7. Taken together, our data support immunoregulatory roles for IFN-ß in the activation and migration of DCs during EAE.

Sex affects immunity.

Sex based differences in immune responses, affecting both the innate and adaptive immune responses, contribute to differences in the pathogenesis of infectious diseases in males and females, the response to viral vaccines and the prevalence of autoimmune diseases. Indeed, females have a lower burden of bacterial, viral and parasitic infections, most evident during their reproductive years. Conversely, females have a higher prevalence of a number of autoimmune diseases, including Sjogren's syndrome, systemic lupus erythematosus (SLE), scleroderma, rheumatoid arthritis (RA) and multiple sclerosis (MS). These observations suggest that gonadal hormones may have a role in this sex differential. The fundamental differences in the immune systems of males and females are attributed not only to differences in sex hormones, but are related to X chromosome gene contributions and the effects of environmental factors. A comprehensive understanding of the role that sex plays in the immune response is required for therapeutic intervention strategies against infections and the development of appropriate and effective therapies for autoimmune diseases for both males and females. This review will focus on the differences between male and female immune responses in terms of innate and adaptive immunity, and the effects of sex hormones in SLE, MS and RA.

Immunoregulatory effects of interferon-ß in suppression of Th17 cells.

To investigate the immunoregulatory effects of interferon (IFN)-ß on CD4+ T cells, we examined the response of CD4+ T cells from IFN-ß(+/+) and IFN-ß(-/-) 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-ß(-/-) T cells compared with IFN-ß(+/+) T cells. Anti-CD3/anti-CD28 antibody stimulation of whole splenocytes or CD4+ T cells from IFN-ß(-/-) mice results in secretion of IL-17A, in contrast to identical stimulation of cells from IFN-ß(+/+) mice, which fails to increase IL-17A production. After CD3/CD28 activation, IFN-ß(-/-) 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-ß(+/+) T cells. Notably, cell surface expression of IL-6R and IL-23R is significantly higher in the IFN-ß(-/-) 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-ß(-/-) mice exhibit a more Th17-primed transcriptome compared with CD4+ T cells from IFN-ß(+/+) mice. Indeed, when CD4+ T cells from IFN-ß(+/+) mice are polarized to Th17 lineage in the presence of IFN-ß, 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-ß(-/-) mice compared with IFN-ß(+/+) mice, and increased numbers of CD4+ T cells in the central nervous system of IFN-ß(-/-) mice, regardless of the stage of disease. Taken together, our data indicate an immunoregulatory role for IFN-ß in the suppression of Th17 cells.