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.
Show 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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