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

Proteasomes catalyze the protein degradation that generates antigenic peptides presented on cell surfaces - a process that in neuroglia (oligodendrocytes and microglia) 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 by elevating regulatory T cell (Treg) populations. We demonstrate that loss of the proteasome adaptor protein Ecm29 alters the efficacy and accuracy of antigens presented on neuronal and neuroglial surfaces. Inducible oligodendroglia- or microglia-conditional Ecm29 knockout (cKO) mice exhibit more severe symptoms of experimental autoimmune encephalomyelitis (EAE) than wild-type counterparts, coincident with reduced numbers of Tregs in spinal cord. MHC-I H2-Db immunopeptidome profiling uncovered self-antigens capable of modulating myelin-reactive T cell proliferation and cytotoxicity. Intraspinal AAV/Olig001-mediated expression of the self-antigen NDUFA1p in neonatal mice proved sufficient to ameliorate EAE and increase the number of CD103+CD8+CD122+ Tregs that recognize NDUFA1p-H2Db complexes. Thus, Ecm29/proteasome-controlled and neuroglia-derived self-antigens modulate CNS immune tolerance.