Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination

Leslie Kirby, Jing Jin, Jaime Gonzalez Cardona, Matthew D. Smith, Kyle A. Martin, Jingya Wang, Hayley Strasburger, Leyla Herbst, Maya Alexis, Jodi Karnell, Todd Davidson, Ranjan Dutta, Joan Goverman, Dwight Bergles and Peter A. Calabresi ()
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Leslie Kirby: Johns Hopkins School of Medicine
Jing Jin: Johns Hopkins School of Medicine
Jaime Gonzalez Cardona: Johns Hopkins School of Medicine
Matthew D. Smith: Johns Hopkins School of Medicine
Kyle A. Martin: Johns Hopkins School of Medicine
Jingya Wang: MedImmune LLC
Hayley Strasburger: Johns Hopkins School of Medicine
Leyla Herbst: Johns Hopkins School of Medicine
Maya Alexis: Johns Hopkins School of Medicine
Jodi Karnell: MedImmune LLC
Todd Davidson: MedImmune LLC
Ranjan Dutta: Cleveland Clinic Foundation
Joan Goverman: University of Washington
Dwight Bergles: Johns Hopkins School of Medicine
Peter A. Calabresi: Johns Hopkins School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-20

Abstract: Abstract Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination.

Date: 2019
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DOI: 10.1038/s41467-019-11638-3

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