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Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients.
- Source :
- Acta Neuropathologica; Sep2017, Vol. 134 Issue 3, p383-401, 19p
- Publication Year :
- 2017
-
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 TCRVβ2CD8 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- T cells
MULTIPLE sclerosis
AUTOANTIGENS
Subjects
Details
- Language :
- English
- ISSN :
- 00016322
- Volume :
- 134
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Acta Neuropathologica
- Publication Type :
- Academic Journal
- Accession number :
- 124728712
- Full Text :
- https://doi.org/10.1007/s00401-017-1744-4