ECM29/proteasome-mediated self-antigen generation by CNS-resident neuroglia promotes regulatory T cell activation

小胶质细胞 细胞生物学 抗原 免疫系统 神经胶质 实验性自身免疫性脑脊髓炎 抗原呈递 T细胞 抗原提呈细胞 髓鞘 神经科学 生物 免疫学 中枢神经系统 炎症
作者
Sheng-Wen Chen,Ying Chu,Chien‐Hsin Chu,Xuan-Dieu Thi Pham,Hang Pong Ng,Chin‐Lin Guo,Pei‐Lin Cheng
出处
期刊:Cell Reports [Cell Press]
卷期号:44 (1): 115161-115161
标识
DOI:10.1016/j.celrep.2024.115161
摘要

Highlights•Neuroglial loss of the proteasome adaptor Ecm29 increases EAE severity•Ecm29 deficiency alters the fidelity of the self-antigen repertoire in tissues•Oligodendrocyte self-antigens drive Treg cell expansion and suppress Teff cell responses•Spinal NDUFA1p delivery ameliorates EAE and expands antigen-specific Treg cellsSummaryProteasomes 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 by elevating regulatory T (Treg) cell 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 to experimental autoimmune encephalomyelitis (EAE) than control counterparts do, coincident with reduced Treg cell populations in the spinal cord. Immunopeptidome profiling identifies self-antigens that modulate myelin-reactive T cell responses. Intraspinal adeno-associated virus (AAV)/Olig001-mediated expression of the self-antigen NDUFA1p ameliorates EAE and expands NDUFA1p-recognizing CD103+CD8+CD122+ Treg cells. Thus, Ecm29/proteasome-controlled, neuroglia-derived self-antigens modulate CNS immune tolerance.Graphical abstract
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