A pro-inflammatory effector-memory T cell program links peripheral EBV priming to CNS autoimmunity

Nikolaj Pagh Kristensen; Thanos Tsaktanis; Sina Frischholz; Jasim Kada Benotmane; Lucia Klotz; Philipp Hilgendorf; M. Grotz; Mariana Sousa; Lasse Frank Voss; Stefan Schattgen; Vanessa Lang; Hannah Reimann; Cosima Storr; Roland Lang; Bernd M. Spriewald; Felix Benedikt Engel; Martin Böttcher; Dimitrios Mougiakakos; Stefanie Schreiber; Dieter Henrik Heiland; Simone Mader; Paul Glyndwr Thomas; Sine Reker Hadrup; Veit Rothhammer; Kilian Schober

doi:10.64898/2026.09.28.753741

ImmunologybioRxivOct 1, 2026

Preprint

A pro-inflammatory effector-memory T cell program links peripheral EBV priming to CNS autoimmunity

Nikolaj Pagh Kristensen iD, Thanos Tsaktanis iD, Sina Frischholz iD, Jasim Kada Benotmane iD, Lucia Klotz, Philipp Hilgendorf iD, M. Grotz iD, Mariana Sousa, Lasse Frank Voss iD, Stefan Schattgen iD, Vanessa Lang, Hannah Reimann iD, Cosima Storr, Roland Lang iD, Bernd M. Spriewald, Felix Benedikt Engel iD, Martin Böttcher iD, Dimitrios Mougiakakos iD, Stefanie Schreiber iD, Dieter Henrik Heiland iD, Simone Mader iD, Paul Glyndwr Thomas iD, Sine Reker Hadrup iD, Veit Rothhammer iD, Kilian Schober iD

Abstract

T and B cell-mediated immunosurveillance of the central nervous system (CNS) can become maladaptive in multiple sclerosis (MS). Epstein-Barr virus (EBV) is a likely driver of MS, yet how exactly EBV-specific T cells contribute remains unclear. We generated an antigen-resolved atlas of blood and cerebrospinal fluid (CSF) T cells from untreated MS patients and controls. T cell clones carrying a GZMK effector-memory program in blood were CSF-biased, particularly in MS, and associated with EBV reactivity. In CSF, EBV-reactive GZMK CD8 T cells engaged B lineage cells. Activated CD8 T cells promoted atypical B cell and plasmablast formation, whereas GZMK-enriched effector-memory cells induced IL-6 and IL-8 release from myeloid cells. Together, these findings identify an infection-imprinted, CNS-biased state and support a model in which EBV-specific CD8 T cells contribute to inflammation through a non-canonical mode of B cell and myeloid cell activation.

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