A new study presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 29 to March 2, in West Palm Beach, Florida, revealed that a small subset of CD8+ T cell clonotypes were preferentially expanded in the cerebrospinal fluid (CSF) among patients with multiple sclerosis (MS), suggesting that they may be involved directly in MS pathology.1
In the study, 38,809 unique T cell clonotypes from the blood and 16,963 unique T cell clonotypes from CSF were identified among 18 patients with MS. Investigators also identified 23 CD8+ T cell clonotypes that were highly and preferentially expanded in the CSF of participants. Notably, the mean frequencies of CSF-enriched CD8+ T cells did not significantly differ between patients with MS and controls (mean +/- SEM = 1.46% +/- 0.19 and 1.18% +/- 0.10, respectively).
Top Clinical Takeaways
- The recent study identified CD8+ T cell clonotypes in the cerebrospinal fluid, suggesting their potential direct involvement in multiple sclerosis pathology.
- Single cell TCR sequencing paired with RNA sequencing was used to define disease-relevant T cell clonotypes, and the study revealed expanded CD8+ T cell clonotypes recognizing viral antigens.
- Two CD8+ T cell clonotypes from different MS patients recognized Epstein–Barr virus (EBV) antigens, supporting the hypothesis of EBV's significant role in multiple sclerosis.
Presented by coauthor Fumie Hayashi, MD, PhD, a postdoctoral fellow in the department of Neurology at University of California, San Francisco, single cell T cell receptor (TCR) sequencing paired with single cell RNA sequencing of the CSF and peripheral blood were performed on a cohort of untreated patients with MS (n = 13) and controls (n = 5). Authors noted that the disease-relevant T cell clonotypes were characterized by the preferential expansion in the CSF relative to peripheral blood. The TCR sequences of CD8+ T cells that met these criteria were cloned and expressed in primary human T cells by CRISPR-mediated TCR knockin. The researchers then had clonal TCR-expressing CD8+ T cells probed for reactivity against nearly 100 immunodominant viral epitopes restricted by 8 different MHC I alleles. In addition, researchers screened CD8+ T cell specificity by peptide:MHC tetramer binding, which was validated by cytokine production.
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The viral antigen discovery pipeline identified several CSF-expanded and enriched CD8+ T cell clonotypes from patients with MS but not controls that recognized different viral antigens. Authors noted that this finding suggests that there are additional unknown antigenic targets that are relevant to MS. Additionally, investors observed 2 different CD8+ T cell clonotypes from different patients with MS that were recognized as Epstein–Barr virus (EBV) antigens, which further support the important role of EBV in MS.
In a recent study published in Proceedings of the National Academy of Sciences, findings demonstrated that T-cells specific for EBV-infected cells are present in high numbers in the CSF of patients with MS at the earliest stages of the disease.2 Senior author J. William Lindsey, MD, professor in the department of neurology with McGovern Medical School at UTHealth Houston, and colleagues, collected blood and CSF samples from 8 patients in the process of MS diagnosis for the analysis. They stimulated cells from the patients’ blood with multiple stimuli and then used RNA sequencing for T-cell receptors to determine which of the stimuli the CSF T-cells were responding to.
Lindsey, who also serves as the Opal C. Rankin professor in neurology at the medical school, recently sat down in an interview with NeurologyLive® to discuss how the abundance of T cells specific for EBV-infected cells in the spinal fluid of patients with MS compared with T cells targeting other infections. He shared his insights on what the study provides into the potential role of T cells in the autoimmune response of MS, specifically those targeting EBV. In addition, Lindsey spoke about the next steps in the research, particularly regarding the investigation of B lymphocytes and the cellular activities of T cells in the spinal fluid of patients with MS.
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REFERENCES
1. Mittl K, Hayashi F, Dandekar R, et al. Probing Viral Specificity of Clonally Expanded CD8+ T Cells in the Cerebrospinal Fluid in Multiple Sclerosis. Presented at ACTRIMS Forum 2024; February 29 to March 2; West Palm Beach, Florida. CE2.1.
2. UTHealth Houston study: EBV-specific T-cells play key role in development of multiple sclerosis. University of Texas Health Science Center at Houston. News Release. Published January 8, 2024. Accessed January 8, 2024. https://www.eurekalert.org/news-releases/1030187
