EBV induces CNS homing of B cells attracting inflammatory T cells

Fabienne Läderach, Ioannis Piteros, Éanna Fennell, Elena Bremer, Mette Last, Sandra Schmid, Lisa Rieble, Caroline Campbell, Isis Ludwig-Portugall, Lea Bornemann, Alexander Gruhl, Klaus Eulitz, Paul Gueguen, Juliane Mietz, Anne Müller, Gaetana Pezzino, Jürgen Schmitz, Guido Ferlazzo, Josef Mautner and Christian Münz ()
Additional contact information
Fabienne Läderach: University of Zürich
Ioannis Piteros: University of Zürich
Éanna Fennell: University of Zürich
Elena Bremer: University of Zürich
Mette Last: Helmholtz Zentrum München
Sandra Schmid: University of Zürich
Lisa Rieble: University of Zürich
Caroline Campbell: University of Zürich
Isis Ludwig-Portugall: Miltenyi Biotec B.V. & Co. KG
Lea Bornemann: Miltenyi Biotec B.V. & Co. KG
Alexander Gruhl: Miltenyi Biotec B.V. & Co. KG
Klaus Eulitz: Miltenyi Biotec B.V. & Co. KG
Paul Gueguen: ETH Zurich/University of Zurich
Juliane Mietz: University of Zürich
Anne Müller: University of Zürich
Gaetana Pezzino: University Hospital Policlinico G.Martino
Jürgen Schmitz: Miltenyi Biotec B.V. & Co. KG
Guido Ferlazzo: University Hospital Policlinico G.Martino
Josef Mautner: Helmholtz Zentrum München
Christian Münz: University of Zürich

Nature, 2025, vol. 646, issue 8083, 171-179

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09378-0

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