T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis
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.
Authors
- Veronika Kana (ORCID: https://orcid.org/0000-0002-9362-3156)
- Galina Yurevna Zheleznyakova (ORCID: https://orcid.org/0000-0003-4660-4523)
- Björn Tackenberg
- Cinzia Esposito
- Daniela Calini
- Daniel Erny (ORCID: https://orcid.org/0000-0001-6000-8838)
- Lucas Pelkmans (ORCID: https://orcid.org/0000-0002-6754-9730)
- Mark D. Robinson (ORCID: https://orcid.org/0000-0002-3048-5518)
- Will Macnair (ORCID: https://orcid.org/0000-0001-6357-0834)
- Imran Fanaswala
- Mohsen Khademi (ORCID: https://orcid.org/0000-0003-0801-1444)
- Maja Jagodic (ORCID: https://orcid.org/0000-0003-0756-889X)
- Yanan Han (ORCID: https://orcid.org/0000-0002-3464-2656)
- Roland Martinꝉ (ORCID: https://orcid.org/0000-0002-0982-1329)
- Pietro Oldrati (ORCID: https://orcid.org/0000-0001-5551-4306)
- Faiez Al Nimer (ORCID: https://orcid.org/0000-0003-0937-5995)
- Ivan Jelčić (ORCID: https://orcid.org/0000-0002-6187-7098)
- Reza Naghavian (ORCID: https://orcid.org/0000-0002-1328-4095)
- Richard Reynolds (ORCID: https://orcid.org/0000-0003-4622-4694)
- Catarina Raposo (ORCID: https://orcid.org/0000-0002-1466-1542)
- Ina Reichen
- Jacobo Sarabia del Castillo (ORCID: https://orcid.org/0000-0001-9656-1416)
- Fredrik Piehl (ORCID: https://orcid.org/0000-0001-8329-5219)
- Mireia Sospedra (ORCID: https://orcid.org/0000-0001-8333-7423)
- Ilijas Jelčić (ORCID: https://orcid.org/0000-0003-3090-7319)
- Dheeraj Malhotra (ORCID: https://orcid.org/0000-0003-4700-4407)
- Zoe Marti
Institutions
- Roche (Switzerland) (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- Karolinska University Hospital (SE)
- University of Zurich (CH)
- Karolinska Institutet (SE)
- University Hospital of Zurich (CH)
- Imperial College London (GB)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102027
- Citations
- 13
- Primary Topic
- Multiple Sclerosis Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 19.13
Funders
- Swedish Foundation for MS Research
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Knut och Alice Wallenbergs Stiftelse
- H2020 European Research Council