T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Self-peptide-dependent autoproliferation (AP) of B and T cells is a key mechanism in MS. Here, we show that pro-inflammatory B-T cell-enriched cell clusters (BTECs) form during AP and mirror features of a germinal center reaction. T-bet+CXCR3+ B cells are the main cell subset amplifying and sustaining their counterpart Th1 cells via interferon (IFN)-γ and are present in highly inflamed meningeal tissue. The underlying B cell activation signature is reflected by epigenetic modifications and receptor-ligand interactions with self-reactive T cells. AP+ CXCR3+ B cells show marked clonal evolution from memory to somatically hypermutated plasmablasts and upregulation of IFN-γ-related genes. Our data underscore a key role of T-bet+CXCR3+ B cells in the pathogenesis of MS in both the peripheral immune system and the CNS compartment, and thus they appear to be involved in both early relapsing-remitting disease and the chronic stage.
Date Issued
2025-03-18
Date Acceptance
2025-02-20
Citation
Cell Reports Medicine, 2025, 6 (3)
ISSN
2666-3791
Publisher
Elsevier BV
Journal / Book Title
Cell Reports Medicine
Volume
6
Issue
3
Copyright Statement
© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40107244
PII: S2666-3791(25)00100-4
Subjects
B-T cell-enriched clusters
BTEC
CXCR3
IFN-gamma
T cells
T-bet+ B cells
autoproliferation
autoreactivity
hyperreactive B-T cell interaction
meninges
multiple sclerosis
self-peptides
Humans
Male
Female
Young Adult
Adult
Middle Aged
Aged
Multiple Sclerosis
T-bet Transcription Factor
Receptors, CXCR3
B-Lymphocytes
Meninges
Cell Proliferation
Th1 Cells
Interferon-gamma
Publication Status
Published
Coverage Spatial
United States
Article Number
102027
Date Publish Online
2025-03-18