Single-cell transcriptome profiling of disease-related lymphocytes in patients with multiple sclerosis
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
This project was based on CRC128-A5, where we investigated disease-related lymphocytes from the cerebrospinal fluid of patients with very early multiple sclerosis (MS) by single cell whole transcriptome next-generation-sequencing (scRNAseq). During this study, we found preliminary indications that the gene expression landscapes were different when samples were collected during an acute relapse as compared to remission, i.e. a quiet stage of MS. Since the switch from relapse to remission and reverse is still an enigmatic feature of MS, we set out to investigate this phenomenon in greater detail in a larger cohort. We tested cells from cerebrospinal fluid (CSF) and peripheral blood from 11 MS patients in relapse, 8 in remission, 6 with radiological isolated syndrome (RIS), and 5 controls with non-inflammatory disease. Of note, all subjects included in this study were untreated. We collaborated with Thomas Korn (TU Munich) and colleagues to investigate provenance transcriptome signatures of CSF-resident CD4+ T cells. T. Korn et al. had studied this topic in great detail in an animal model of MS. Using data from our human cohort, we could identify parallel gene expression patterns. In one of the clusters, we found high expression of CXCR6 and other molecules indicating that these cells were primed in the inguinal lymph nodes. In the other clusters, we found gene-expression signatures indicative for priming in mesenteric lymph nodes. These data may be a hint that the site of T cell priming may also play a role in the pathogenesis of human MS. Comparison of transcriptomes from CSF cells isolated in remission, relapse, RIS, and non-inflammatory controls confirmed our initial preliminary data. We found significant differences in the gene expression patterns of several cell types. When analyzing CD8+ T cells, which are the dominant lymphocyte population in inflammatory lesions of MS patients and therefore most likely highly disease-relevant, we could distinguish 10 subclusters including naïve, MAIT, effector, and antigen-experienced tissue resident memory (TRM) T cells. In particular, we saw striking differences between MS patients in remission and relapse in two TRM subclusters. One of these TRM subclusters contained high numbers of downregulating T cells and was dominant in remission only. These downregulating T cells were not prominent during relapses. In this subcluster, we found strong type-I interferon signatures, which were much less pronounced during relapse. This is particularly interesting because interferon-beta, which is a commonly used in the treatment of MS, belongs to the type-I interferon group. Thus, one may speculate that endogenous type-I interferons may calm disease progression in MS and that this is the rational basis of the highly efficient interferon-beta therapies.
Publications
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(2021) Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity. Nat. Immunol. 22:880-891
Hiltensperger, M., Beltrán, E., Kant, R., Tyystlärvi, S., Lepennetier, G., Domínguez Moreno, H., Bauer, I.J., Grassmann, S., Jarosch, S., Schober, K., Buchholz, V.R., Kenet, S., Gasperi, C., Öllinger, R., Rad, R., Muschaweckh, A., Sie, C., Aly, L., Knier, B., Garg, G., Afzali, A.M., Gerdes, L.A., Kümpfel, T., Franzenburg, S., Kawakami, N., Hemmer, B., Busch, D.H., Misgeld, T., Dornmair, K., and Korn, T
