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Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis
Eduardo Beltrán, … , Reinhard Hohlfeld, Klaus Dornmair
Eduardo Beltrán, … , Reinhard Hohlfeld, Klaus Dornmair
Published September 30, 2019
Citation Information: J Clin Invest. 2019;129(11):4758-4768. https://doi.org/10.1172/JCI128475.
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Research Article Immunology Neuroscience

Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis

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Abstract

Multiple sclerosis (MS) is a disabling disease of the CNS. Inflammatory features of MS include lymphocyte accumulations in the CNS and cerebrospinal fluid (CSF). The preclinical events leading to established MS are still enigmatic. Here we compared gene expression patterns of CSF cells from MS-discordant monozygotic twin pairs. Six “healthy” co-twins, who carry a maximal familial risk for developing MS, showed subclinical neuroinflammation (SCNI) with small MRI lesions. Four of these subjects had oligoclonal bands (OCBs). By single-cell RNA sequencing of 2752 CSF cells, we identified clonally expanded CD8+ T cells, plasmablasts, and, to a lesser extent, CD4+ T cells not only from MS patients but also from subjects with SCNI. In contrast to nonexpanded T cells, clonally expanded T cells showed characteristics of activated tissue-resident memory T (TRM) cells. The TRM-like phenotype was detectable already in cells from SCNI subjects but more pronounced in cells from patients with definite MS. Expanded plasmablast clones were detected only in MS and SCNI subjects with OCBs. Our data provide evidence for very early concomitant activation of 3 components of the adaptive immune system in MS, with a notable contribution of clonally expanded TRM-like CD8+ cells.

Authors

Eduardo Beltrán, Lisa Ann Gerdes, Julia Hansen, Andrea Flierl-Hecht, Stefan Krebs, Helmut Blum, Birgit Ertl-Wagner, Frederik Barkhof, Tania Kümpfel, Reinhard Hohlfeld, Klaus Dornmair

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Figure 6

Violin plots show gene expression of CD8+ T cells on the single-cell level.

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Violin plots show gene expression of CD8+ T cells on the single-cell lev...
Each dot represents a single cell. Statistically significant gene expression is observed only if a violin-shaped fitting area can be calculated. (A) The homing marker S1PR1 is expressed on all T cells but is downregulated when a cell adopts a TRM phenotype. This is only the case for expanded CD8+ T cells from MS patients. (B) The TRM marker CXCR6 is upregulated only in expanded CD8+ T cells from MS and Enc patients. (C) The marker CXCL16 is the sole ligand of CXCR6. It is upregulated only in DCs and monocytes. (D) CXCL16 is expressed in DCs (left panel) and monocytes (right panel) from all patient groups.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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