Antigen specificity of clonally enriched CD8+ T cells in multiple sclerosis

Fumie Hayash, Kristen Mittl, Ravi Dandekar, Josiah Gerdts, Ebtesam Hassan, Ryan D. Schuber, Lindsay Oshir, Rita Loudermilk, Ariele Greenfield, Danillo G. August, Gregory Havton, Shriya Anumarlu, Arhan Surapaneni, Akshaya Ramesh, Edwina Tran, Kanishka Koshal, Kerry Kizer, Joanna Dreux, Alaina K. Cagalingan, Florian Schustek, Lena Flood, Tamson Moore, Lisa L. Kirkemo, Isabelle J. Fisher, Tiffany Cooper, Meagan Harms, Refujia Gomez, University of California, San Francisco MS-EPIC Team, Claire D. Clelland, Leah Sibener, Bruce A. C. Cree, Stephen L. Hauser, Jill A. Hollenbac , Marvin Gee, Michael R. Wilson , Scott S. Zamvil & Joseph J. Sabatino Jr

Nat Immunol. | 2026 | 27 | 490-502

CD8+ T cells are the dominant clonally expanded lymphocyte population in multiple sclerosis (MS) lesions but their clonal identity, function and antigen specificity are not well understood. A comprehensive single-cell RNA-sequencing and T cell receptor-sequencing analysis of the cerebrospinal fluid and blood from individuals in the MS and control cohorts revealed a subset of 23 highly expanded and activated CD8+ T cell clonotypes that were enriched predominantly in the cerebrospinal fluid in the MS cohort. Using unbiased and targeted antigen discovery approaches, six CD8+ T cell clonotypes recognizing Epstein–Barr virus (EBV) antigens and multiple novel mimotopes were identified. Although the majority of mimotopes did not elicit functional responses, three of the expanded CD8+ T cell receptors from patients with MS were reactive to EBV. EBV DNA and transcripts were detected in cerebrospinal fluid, including in patients with MS who had highly expanded EBV-specific CD8+ T cells. These findings shed vital insight into the role of CD8+ T cells in MS and support an important role of EBV in MS immunopathology.