EBV induces CNS homing of B cells attracting inflammatory T cells

  • Nature. 2025 Aug 6. doi: 10.1038/s41586-025-09378-0.
Fabienne Läderach  #  1 ,  Ioannis Piteros  #  1 ,  Éanna Fennell  1  2 ,  Elena Bremer  1 ,  Mette Last  3 ,  Sandra Schmid  1 ,  Lisa Rieble  1 ,  Caroline Campbell  1 ,  Isis Ludwig-Portugall  4 ,  Lea Bornemann  5 ,  Alexander Gruhl  5 ,  Klaus Eulitz  4 ,  Paul Gueguen  6 ,  Juliane Mietz  7 ,  Anne Müller  1 ,  Gaetana Pezzino  8 ,  Jürgen Schmitz  9 ,  Guido Ferlazzo  8  10  11 ,  Josef Mautner  3 ,  Christian Münz  12
Affiliations
  • 1. Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
  • 2. School of Medicine, Bernal Institute, Health Research Institute, Limerick Digital Cancer Research Centre, University of Limerick, Limerick, Ireland.
  • 3. Institute of Virology, Helmholtz Zentrum München, Munich, Germany.
  • 4. Miltenyi Biotec B.V. & Co. KG, Teterow, Germany.
  • 5. Miltenyi Biotec B.V. & Co. KG, Bielefeld, Germany.
  • 6. Functional Genomics Center, ETH Zurich/University of Zurich, Zurich, Switzerland.
  • 7. Cellular Immunotherapy, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
  • 8. Division of Clinical Pathology, University Hospital Policlinico G.Martino, Messina, Italy.
  • 9. Miltenyi Biotec B.V. & Co. KG, Bergisch-Gladbach, Germany.
  • 10. Department of Experimental Medicine, University of Genoa, Genova, Italy.
  • 11. Unit of Experimental Pathology and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico San Martino, Genova, Italy.
  • 12. Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland. [email protected].
  • # Contributed equally.
PMID: 40770101 DOI: 10.1038/s41586-025-09378-0
Abstract

Epidemiological data have identified Epstein-Barr virus (EBV) Infection as the main environmental risk factor for multiple sclerosis, the predominant autoimmune disease of the central nervous system (CNS)1. However, how EBV Infection initiates multiple sclerosis pathogenesis remains unclear. Here we demonstrate that EBV expands oligoclonal T-bet+CXCR3+ B cells that home to the CNS in humanized mice. Effector memory CD8+ T cells and CD4+ TH1 cells as well as CD4+ TH17 cells co-migrate to the brain of EBV-infected humanized mice. T-bet+CXCR3+ B cells can colonize submeningeal brain regions in the absence of Other lymphocytes and attract T cells. Depletion of B cells with rituximab or blocking of CXCR3 significantly decreases lymphocyte infiltration into the CNS. Thus, we suggest that symptomatic primary EBV Infection generates B cell subsets that gain access to the CNS, attract T cells and thereby initiate multiple sclerosis.

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