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

Mittl, K.; Hayashi, F.; Dandekar, R.; Schubert, R. D.; Gerdts, J.; Oshiro, L.; Loudermilk, R.; Greenfield, A. L.; Augusto, D. G.; Ramesh, A.; Tran, E.; Koshal, K.; Kizer, K.; Dreux, J.; Cagalingan, A.; Schustek, F.; Flood, L.; Moore, T.; Kirkemo, L. L.; Cooper, T.; Harms, M.; Gomez, R.; University of California, San Francisco MS-EPIC Team,; Sibener, L.; Cree, B. A. C.; Hauser, S. L.; Hollenbach, J. A.; Gee, M.; Wilson, M. R.; Zamvil, S.; Sabatino, J. J.

doi:10.1101/2024.09.07.611010

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bioRxiv · 10.1101/2024.09.07.611010

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

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Abstract

CD8+ T cells are the dominant lymphocyte population in multiple sclerosis (MS) lesions where they are highly clonally expanded. The clonal identity, function, and antigen specificity of CD8+ T cells in MS are not well understood. Here we report a comprehensive single-cell RNA-seq and T cell receptor (TCR)-seq analysis of the cerebrospinal fluid (CSF) and blood from a cohort of treatment-naive MS patients and control participants. A small subset of highly expanded and activated CD8+ T cells were enriched in the CSF in MS that displayed high activation, cytotoxicity and tissue-homing transcriptional profiles. Using a combination of unbiased and targeted antigen discovery approaches, MS-derived CD8+ T cell clonotypes recognizing Epstein-Barr virus (EBV) antigens and multiple novel mimotopes were identified. These findings shed vital insight into the role of CD8+ T cells in MS and pave the way towards disease biomarkers and therapeutic targets. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/611010v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1a0b738org.highwire.dtl.DTLVardef@5cf5c2org.highwire.dtl.DTLVardef@10abdccorg.highwire.dtl.DTLVardef@32c7b2_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical SummaryC_FLOATNO Created in BioRender. Sabatino, J. (2024) BioRender.com/e66l598 C_FIG

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Mittl, K., Hayashi, F., Dandekar, R., Schubert, R. D., Gerdts, J., Oshiro, L., Loudermilk, R., Greenfield, A. L., Augusto, D. G., Ramesh, A., Tran, E., Koshal, K., Kizer, K., Dreux, J., Cagalingan, A., Schustek, F., Flood, L., Moore, T., Kirkemo, L. L., Cooper, T., Harms, M., Gomez, R., University of California, San Francisco MS-EPIC Team,, Sibener, L., Cree, B. A. C., Hauser, S. L., Hollenbach, J. A., Gee, M., Wilson, M. R., Zamvil, S., Sabatino, J. J.. 2024-09-07. Antigen-specificity of clonally-enriched CD8+ T cells in multiple sclerosis. https://doi.org/10.1101/2024.09.07.611010

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