Multiple sclerosis (MS) is characterized by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs). We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells. Surprisingly, EAE-specific OL lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context. Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells. Finally, we demonstrate that OPCs can phagocytose and that MHC-II-expressing OPCs can activate memory and effector CD4-positive T cells. Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.
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We would like to thank A. Nanni, A. Moshref, Tony Jimenez-Beristain and J. Söderlund for laboratory management and support. We thank Eukaryotic Single Cell Genomics Facility, WABI Long Term Bioinformatic Support (Leif Wigge) at SciLifeLab, the FACS facilities at CMB (B. Panagel), Science for Life Laboratory, the National Genomics Infrastructure and Uppmax for providing assistance in massive parallel sequencing and computational infrastructure. We wish to acknowledge A. G. Rothfuchs for advice and reagents, M. Jagodic for advice, M. Bartosovic for assistance, R. Berglund and M. N’diaye for providing the tools to perform the phagocytosis experiments. The bioinformatics computations were performed on resources provided by the Swedish National Infrastructure for Computing at UPPMAX, Uppsala University. Postmortem MS tissue used for IHC was provided via a UK prospective donor scheme with full ethical approval from the UK Multiple Sclerosis Tissue Bank (MREC/02/02/39). D.P.V. would like to acknowledge the University of Sydney HPC service for providing HPC resources that have contributed to the research reported in this paper. This work was supported in part by a University of Sydney HPC Grand Challenge Award. D.P.V. was supported in part by a Boehringer Ingelheim Travel Grant. C.f.-C. is funded by a Wellcome Trust Investigator award. A.W. is funded by UK Multiple Sclerosis Society. S.J. is funded by European Union, Horizon 2020, Marie-Skłodowska Curie Actions (grant no. EC 789492); A.M.F. by the European Committee for Treatment and Research of Multiple Sclerosis (ECTRIMS). E.A. is funded by European Union, Horizon 2020, Marie-Skłodowska Curie Actions (grant no. SOLO 794689). Work in G.C.-B.’s research group was supported by Swedish Research Council (grant no. 2015-03558), European Union (Horizon 2020 Research and Innovation Programme/European Research Council Consolidator Grant EPIScOPE, grant agreement 681893), Swedish Brain Foundation (grant no. FO2017-0075), Ming Wai Lau Centre for Reparative Medicine, Petrus och Augusta Hedlunds Foundation (grant nos. M-2014-0041 and M-2016-0428) and Karolinska Institutet.
The G.C.-B., A.W. and C.f.-C. research groups have received funding from F. Hoffmann–La Roche, Ltd. for other research projects in this area.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–9
MOL2 cells express MHC-II genes
OPCs express MHC-II genes
OL lineage cells express MHC-II genes
OL lineage cells express MHC-II genes
OL lineage cells express MHC-II genes and few Aif1 molecules
OL lineage cells express MHC-II genes
Microglia processes touch OL lineage cells
MHC-II positive cells surround OL lineage cells in human MS patient samples
OL lineage cells from human MS patient samples express MHC-II genes
Differential gene expression and gene module association
Splicing events and exon inclusion or exclusion events
Differential gene expression between CTRL and EAE in MOLs and OPCs
Non-MHC MS susceptibility genes expressed in microglia and OPCs in EAE and CTRL and significant differential expression of these genes across the major level 1 cluster
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Falcão, A.M., van Bruggen, D., Marques, S. et al. Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Nat Med 24, 1837–1844 (2018). https://doi.org/10.1038/s41591-018-0236-y
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