Antigen specificity of clonally enriched CD8+ T cells in multiple sclerosis
CD8<sup>+</sup> 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<sup>+</sup> T cell clonotypes that were enriched predominantly in the cerebrospinal fluid in the MS cohort. Using unbiased and targeted antigen discovery approaches, six CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cells. These findings shed vital insight into the role of CD8<sup>+</sup> T cells in MS and support an important role of EBV in MS immunopathology.
Authors
- Samuel J. Pleasure (ORCID: https://orcid.org/0000-0001-8599-1613)
- Ryan Schubert (ORCID: https://orcid.org/0000-0002-3132-5831)
- Simone Sacco (ORCID: https://orcid.org/0000-0001-8789-3099)
- Kanishka Koshal (ORCID: https://orcid.org/0000-0002-0612-0738)
- Adam Renschen (ORCID: https://orcid.org/0000-0002-8042-6823)
- Richard Cuneo
- S. L. Hauser
- Mary E. Wilson (ORCID: https://orcid.org/0000-0001-8680-7275)
- Joanna Dreux
- Akshaya Ramesh (ORCID: https://orcid.org/0000-0003-0205-0688)
- Meagan Harms
- Joseph J. Sabatino (ORCID: https://orcid.org/0000-0002-6804-7441)
- Marvin H. Gee (ORCID: https://orcid.org/0000-0002-2553-2797)
- Ahmed Abdelhak (ORCID: https://orcid.org/0000-0001-9731-4169)
- Lisa L. Kirkemo (ORCID: https://orcid.org/0000-0003-1686-6987)
- Isabelle Fisher (ORCID: https://orcid.org/0009-0000-8558-118X)
- Danillo G. Augusto (ORCID: https://orcid.org/0000-0001-5665-8547)
- Ariele L. Greenfield (ORCID: https://orcid.org/0000-0002-4117-8986)
- Riley M. Bove (ORCID: https://orcid.org/0000-0002-2034-8800)
- Lena Flood
- Tamson V. Moore (ORCID: https://orcid.org/0000-0003-3770-3503)
- Tiffany Cooper (ORCID: https://orcid.org/0009-0003-4584-0994)
- Leah V. Sibener (ORCID: https://orcid.org/0000-0001-9737-8517)
- Nico Papinutto (ORCID: https://orcid.org/0000-0003-2184-4782)
- Kristen Mittl
- Fumie Hayashi (ORCID: https://orcid.org/0000-0002-7754-3770)
- Alaina Cagalingan
- Claire D. Clelland (ORCID: https://orcid.org/0000-0002-9112-2278)
- Ravi Dandekar (ORCID: https://orcid.org/0000-0002-2930-3043)
- R. W. Loudermilk
- Scott Zamvil
- Edwina B. Tran
- Gregory C Havton
- Florian Schustek
- Josiah Gerdts
- Joanne Guo
- Kerry Kizer
- Lindsay Oshiro
- Anna Sindalovsky
- Ari J. Green
- Roland G. Henry
- Harkee Halait
- Jill A. Hollenbach
- Adam Santaniello
- Sasha Gupta
- Refujia Gomez
- Stacy Caillier
- Bruce A. C. Cree
- Shriya Anumarlu
- Jeffrey Gelfand
- Ebtesam Hassan
- Jorge R. Oksenberg
- Arhan Surapaneni
Institutions
- University of North Carolina at Charlotte (US)
- University of California, Los Angeles (US)
- University of California, San Francisco (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-02-05
- DOI
- https://doi.org/10.1038/s41590-025-02412-3
- Primary Topic
- Multiple Sclerosis Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00