The impact of IL-27 on human T cells is altered in multiple sclerosis patients

Abstract

Abstract Interleukin-27 (IL-27) exhibits pro- and anti-inflammatory properties. Although this cytokine dampens the severity of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), whether IL 27 contributes to the pathobiology of MS remains unclear. We detected the IL-27 receptor (IL-27R) on brain-infiltrating T cells in MS tissues suggesting that they are susceptible to this cytokine. Notably, beneficial effects of MS immunomodulatory therapies are associated with IL-27 induction. We compared blood samples from untreated MS patients to healthy donors (HC) for i) serum levels of IL-27 and expression of IL-27R by T cells and ii) effects of IL-27 on phenotype and functions of T cells. Reduced proportions of CD4 T cells but greater percentages of CD8 T cells expressed IL-27R in MS patients compared to HC. IL-27 triggered phosphorylation of STAT1 (pSTAT1) and STAT3 (pSTAT3) in all T cell subsets; similar levels of pSTAT1 were induced in T cells from MS and HC. In contrast, increased proportions of CD4 and CD8 T cells exhibited pSTAT3 in response to IL-27 compared to cells from HC. Moreover, addition of IL-27 to activated T cells significantly decreased the percentages of GM-CSF or IL-17 producing CD4 and CD8 T cells from MS patients but had a minimal impact on HC’s cells. Finally, sera from MS patients contained elevated amounts of soluble IL-27 and IL-27Rα (a natural IL-27 antagonist) compared to HC. Our results reveal that IL-27 has an enhanced impact on T cells from MS patients, which could contribute to dampen key immune responses (e.g. GM-CSF, IL-17) associated with this inflammatory/autoimmune disease. However, elevated in vivo levels of its natural antagonist could hinder IL-27-mediated anti-inflammatory properties.