Mittl Kristen, Hayashi Fumie, Dandekar Ravi, Schubert Ryan D, Gerdts Josiah, Oshiro Lindsay, Loudermilk Rita, Greenfield Ariele, Augusto Danillo G, Ramesh Akshaya, Tran Edwina, Koshal Kaniskha, Kizer Kerry, Dreux Joanna, Cagalingan Alaina, Schustek Florian, Flood Lena, Moore Tamson, Kirkemo Lisa L, Cooper Tiffany, Harms Meagan, Gomez Refujia, Sibener Leah, Cree Bruce A C, Hauser Stephen L, Hollenbach Jill A, Gee Marvin, Wilson Michael R, Zamvil Scott S, Sabatino Joseph J
UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, USA.
Department of Biological Sciences, The University of North Carolina at Charlotte, NC, USA.
bioRxiv. 2024 Oct 17:2024.09.07.611010. doi: 10.1101/2024.09.07.611010.
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-naïve 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.
CD8+ T细胞是多发性硬化症（MS）病变中占主导地位的淋巴细胞群体，在这些病变中它们高度克隆性扩增。MS中CD8+ T细胞的克隆身份、功能和抗原特异性尚未得到充分了解。在此，我们报告了对一组未经治疗的MS患者和对照参与者的脑脊液（CSF）和血液进行的全面单细胞RNA测序和T细胞受体（TCR）测序分析。一小部分高度扩增和活化的CD8+ T细胞在MS患者的脑脊液中富集，这些细胞表现出高活化、细胞毒性和组织归巢转录谱。通过结合无偏和靶向抗原发现方法，鉴定出了识别爱泼斯坦-巴尔病毒（EBV）抗原和多种新型模拟表位的MS来源的CD8+ T细胞克隆型。这些发现为CD8+ T细胞在MS中的作用提供了重要见解，并为疾病生物标志物和治疗靶点铺平了道路。
