ECM29/Proteasome-Mediated Self-Antigen Generation by CNS-Resident Neuroglia Promotes Regulatory T Cell Activation

Proteasomes generate antigenic peptides presented on cell surfaces - a process that in neuroglia is highly responsive to external stimuli. However, the function of the self-antigens presented by CNS parenchymal cells remains unclear. Here, we report that the fidelity of neuroglial self-antigens is crucial to suppress encephalitogenic T cell responses via elevating regulatory T cell (Treg) populations. We demonstrate that loss of the proteasome adaptor protein Ecm29 alters the efficacy and accuracy of antigen generation. Inducible oligodendroglia- or microglia conditional Ecm29 knockout mice exhibit higher susceptibility of experimental autoimmune encephalomyelitis (EAE) than control counterparts, coincident with reduced Tregs populations in spinal cord. Immunopeptidome profiling identifies self-antigens that modulate myelin-reactive T cell responses. Intraspinal AAV/Olig001-mediated expression of the self-antigen NDUFA1p ameliorated EAE and expands NDUFA1p-recognizing CD103+CD8+CD122+ Tregs. Thus, Ecm29/proteasome-controlled, neuroglia-derived self-antigens modulate CNS immune tolerance. To assess the influences of oligodendroglial Ecm29 cKO on proinflammatory response in the CNS parenchyma, we conducted transcriptomic analysis on spinal cord and brain tissues affected by EAE. Comparitive gene expression profilling RNA-seq data for the O4+ oligodendrocytes/Schwann isolated from the oligodendroglial Ecm29 cKO mice.