Antigen specificity of clonally enriched CD8+ T cells in multiple sclerosis
Fumie Hayashi, Kristen Mittl, Ravi Dandekar, Josiah Gerdts, Ebtesam Hassan, Ryan Schubert, Lindsay Oshiro, R. W. Loudermilk, Ariele L. Greenfield, Danillo G. Augusto, Gregory C Havton, Shriya Anumarlu, Arhan Surapaneni, Akshaya Ramesh, Edwina B. Tran, Kanishka Koshal, Kerry Kizer, Joanna Dreux, Alaina Cagalingan, Florian Schustek, Lena Flood, Tamson V. Moore, Lisa L. Kirkemo, Isabelle Fisher, Tiffany Cooper, Meagan Harms, Refujia Gomez, Ahmed Abdelhak, Sergio Baranzini, Riley Bove, Stacy Caillier, Richard Cuneo, Jeffrey M. Gelfand, Ari J. Green, Joanne Guo, Sasha Gupta, Harkee Halait, Roland G. Henry, Jill A. Hollenbach, Jorge R. Oksenberg, Nico Papinutto, Samuel J. Pleasure, Adam Renschen, Simone Sacco, Adam Santaniello, Anna Sindalovsky, Claire D. Clelland, Leah V. Sibener, Bruce A. C. Cree, S. L. Hauser, Jill A. Hollenbach, Marvin H. Gee, Michael R. Wilson, Scott Zamvil, Joseph J. Sabatino
Abstract
Abstract 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.