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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月5日

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  • Fumie Hayashi,
  • Kristen Mittl,
  • Ravi Dandekar,
  • Josiah Gerdts,
  • Ebtesam Hassan,
  • Ryan D. Schubert,
  • Lindsay Oshiro,
  • Rita Loudermilk,
  • Ariele Greenfield,
  • Danillo G. Augusto,
  • 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,
  • Ahmed Abdelhak,
  • Sergio Baranzini,
  • Riley Bove,
  • Stacy Caillier,
  • Richard Cuneo,
  • Jeffrey Gelfand,
  • Ari Green,
  • Joanne Guo,
  • Sasha Gupta,
  • Harkee Halait,
  • Roland G. Henry,
  • Jill A. Hollenbach,
  • Jorge R. Oksenberg,
  • Nico Papinutto,
  • Samuel Pleasure,
  • Adam Renschen,
  • Simone Sacco,
  • Adam Santaniello,
  • Anna Sindalovsky,
  • Claire D. Clelland,
  • Leah Sibener,
  • Bruce A. C. Cree,
  • Stephen L. Hauser,
  • Jill A. Hollenbach,
  • Marvin Gee,
  • Michael R. Wilson,
  • Scott S. Zamvil,
  • Joseph J. Sabatino Jr

摘要

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.