Multiple sclerosis is a T cell-mediated demyelinating disease of the central nervous system. Interleukin-17-producing T helper cells, named Th17 cells, represent a novel CD4+ T cell effector subset involved in the response against extracellular pathogens. In addition, Th17 cells are pathogenic in several animal models of autoimmune disease, including the animal model for multiple sclerosis, but their function in multiple sclerosis remains to be elucidated. In this study, we analysed the frequency and the phenotype of Th17 cells in the cerebrospinal fluid and peripheral blood of multiple sclerosis patients. We show that the frequency of Th17 cells is significantly higher in the cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis during relapse, in comparison to relapsing-remitting patients in remission or to patients with other non-inflammatory neurological diseases. Similarly, in patients with clinically isolated syndrome during their first neurological episode, Th17 cells are more abundant than in clinically isolated syndrome patients with no acute symptoms. Patients with inflammatory neurological diseases other than multiple sclerosis also showed increased frequency of Th17 cells compared to patients with no inflammatory diseases. To assess a potential pathological impact of Th17 cells in disease, we generated T cell clones from the cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. We found that Th17 clones expressed higher basal levels of the activation markers CD5, CD69, CD2 and human leukocyte antigen-DR as well as of the CD28-related family of co-stimulatory molecules, when compared to Th1 clones, and confirmed these findings with ex vivo human T cells. Molecules involved in T cell adhesion to endothelium, such as CD49d, CD6 and the melanoma cell adhesion molecule, were also more abundant on the Th17 than on the Th1 cells. Furthermore, functional assays showed that Th17 clones were more prone than Th1 clones to melanoma cell adhesion molecule-mediated adhesion to endothelial cells, and that Th17 cells had a higher proliferative capacity and were less susceptible to suppression than Th1 cells. Altogether our data suggest that Th17 cells display a high pathogenic potential and may constitute a relevant pathogenic subset in multiple sclerosis.

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Th17 cells are involved in the defense against bacteria and fungi and play a prominent role in the pathogenesis of autoimmune diseases, but research on human Th17 cells is hindered due to the lack of a surface marker. In this study, we report that a subset of human and mouse CD4+ T cells as well as human Th17 T cell clones express IL-17A on their surface upon stimulation. Correlation of surface IL-17A expression with intracellular IL-17A production and with RORγt mRNA expression identified surface IL-17A as a specific marker for human and mouse Th17 cells. Phenotype characterization of ex vivo CD4+ IL-17A+ cells showed that the chemokines CCR6 and CCR4, costimulatory molecules, as well as CD2 and CD49d were more prominently expressed on these cells than in surface IL-17A− cells, supporting the concept of Th17 cells as a potent inflammatory effector subtype. In addition, we generated human Th1, Th1/17 (producing both IFN-γ and IL-17A), and Th17 T cell clones based on single cell sorting of surface IL-17A−, IL-17Aint, and IL-17Ahigh CD4+ T cells, respectively, and showed the plasticity of the double producing clones to the cytokine milieu. The identification of surface IL-17A as a marker for Th17 cells should facilitate research on this subset.

Betamethasone administered to the mother before birth reaches the fetal thymus. Prenatal betamethasone results in massive loss of developing thymocytes. The effects of betamethasone on thymus development are visible for several days. Human thymocytes are also sensitive to low doses of betamethasone. Altered thymocyte development around birth may have an effect on the immune system.