Chandelier
Senior Member (Voting Rights)
A pro-inflammatory effector-memory T cell program links peripheral EBV priming to CNS autoimmunity
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.
Web | DOI | bioRxiv | Open Access
Kristensen, Nikolaj Pagh; Tsaktanis, Thanos; Frischholz, Sina; Benotmane, Jasim K.; Klotz, Lucia; Hilgendorf, Philipp; Grotz, Myriam; Sousa, Mariana; Voss, Lasse F.; Schattgen, Stefan; Lang, Vanessa; Reimann, Hannah; Storr, Cosima; Lang, Roland; Spriewald, Bernd; Engel, Felix B.; Boettcher, Martin; Mougiakakos, Dimitrios; Schreiber, Stefanie; Heiland, Dieter H.; Mader, Simone; Thomas, Paul G.; Hadrup, Sine Reker; Rothhammer, Veit; Schober, Kilian
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.
Web | DOI | bioRxiv | Open Access