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Acta Neuropathologica
Published in: Acta Neuropathologica 3/2017

Open Access 01-09-2017 | Original Paper

Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients

Authors: Gijsbert P. van Nierop, Marvin M. van Luijn, Samira S. Michels, Marie-Jose Melief, Malou Janssen, Anton W. Langerak, Werner J. D. Ouwendijk, Rogier Q. Hintzen, Georges M. G. M. Verjans

Published in: Acta Neuropathologica | Issue 3/2017

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Abstract

T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry. T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry. Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WML. WML-derived CD8+ T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137). The same lesions also contained higher CD8+ T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed. The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8+ T cells, correlated between TCL generated from anatomically separated WML of the same MS patient, but not between paired NAWM and WML. Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8+ T-cell reactivity was detected in multiple WML-derived TCL towards autologous Epstein–Barr virus (EBV) infected B cells (autoBLCL). In one MS patient, the T-cell response towards autoBLCL in paired intra-lesional TCL was dominated by TCRVβ2+CD8+ T cells, which were localized in the parenchyma of the respective tissues expressing a polarized TCR and CD8 expression suggesting immunological synapse formation in situ. Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients.
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Metadata
Title
Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients
Authors
Gijsbert P. van Nierop
Marvin M. van Luijn
Samira S. Michels
Marie-Jose Melief
Malou Janssen
Anton W. Langerak
Werner J. D. Ouwendijk
Rogier Q. Hintzen
Georges M. G. M. Verjans
Publication date
01-09-2017
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 3/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-017-1744-4

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