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

Kristensen, N. P.; Tsaktanis, T.; Frischholz, S.; Benotmane, J. K.; Klotz, L.; Hilgendorf, P.; Grotz, M.; Sousa, M.; Voss, L. F.; Schattgen, S.; Lang, V.; Reimann, H.; Storr, C.; Lang, R.; Spriewald, B.; Engel, F. B.; Boettcher, M.; Mougiakakos, D.; Schreiber, S.; Heiland, D. H.; Mader, S.; Thomas, P. G.; Hadrup, S. R.; Rothhammer, V.; Schober, K.

doi:10.64898/2026.09.28.753741

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bioRxiv · 10.64898/2026.09.28.753741

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

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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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Kristensen, N. P., Tsaktanis, T., Frischholz, S., Benotmane, J. K., Klotz, L., Hilgendorf, P., Grotz, M., Sousa, M., Voss, L. F., Schattgen, S., Lang, V., Reimann, H., Storr, C., Lang, R., Spriewald, B., Engel, F. B., Boettcher, M., Mougiakakos, D., Schreiber, S., Heiland, D. H., Mader, S., Thomas, P. G., Hadrup, S. R., Rothhammer, V., Schober, K.. 2026-10-01. A pro-inflammatory effector-memory T cell program links peripheral EBV priming to CNS autoimmunity. https://doi.org/10.64898/2026.09.28.753741

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