Brain Advance Access published online on November 23, 2009
Brain, doi:10.1093/brain/awp289
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Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis
1 Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany 2 Department of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany 3 Graduate School of Cellular and Molecular Neuroscience, University of Tuebingen, Germany 4 Department of Neurology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
Correspondence to:
Eva Tolosa, Department of Immunology, University Medical Centre Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany E-mail: etolosa{at}uke.uni-hamburg.de
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.
Key Words: multiple sclerosis; T cells; IL-17
Abbreviations:
CFSE, carboxyfluorescein succinimidyl ester; CIS, patient group with clinically isolated syndrome and neurologically stable; CIS/R, patient group showing signs of their first neurological event; CTLA, cytotoxic T-lymphocyte antigen; ICOS, inducible T-cell costimulator; IFN-
, gamma interferon; IL, interleukin; MCAM, melanoma cell adhesion molecule; PBMC, peripheral blood mononuclear cells; PD-1, programmed death-1 receptor; RR-MS, patient group in remission phase of relapsing-remitting multiple sclerosis; RR-MS/R, patient group with relapsing-remitting multiple sclerosis showing acute relapse; TCC, T cell clone; Th, T helper
Received April 3, 2009. Revised September 23, 2009. Accepted September 25, 2009.