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.