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. Overall design: 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.

蛋白酶体（Proteasome）可生成呈递于细胞表面的抗原肽——这一过程在神经胶质细胞中对外界刺激具有高度响应性。然而，中枢神经系统（Central Nervous System, CNS）实质细胞所呈递的自身抗原的功能仍不明确。本研究发现，神经胶质细胞自身抗原的保真度对于通过上调调节性T细胞（regulatory T cell, Treg）数量以抑制致脑炎T细胞应答至关重要。本研究证实，蛋白酶体衔接蛋白Ecm29的缺失会改变抗原生成的效率与准确性。诱导性少突胶质细胞或小胶质细胞条件性敲除Ecm29的小鼠，相较于对照组小鼠，对实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis, EAE）的易感性更高，同时其脊髓内的Treg数量也有所减少。免疫肽组学分析鉴定出了可调控髓鞘反应性T细胞应答的自身抗原。通过脊髓内腺相关病毒（adeno-associated virus, AAV)/Olig001介导的自身抗原NDUFA1p表达，可缓解EAE并扩增识别NDUFA1p的CD103+CD8+CD122+ Treg细胞。综上，由Ecm29/蛋白酶体调控的、源自神经胶质细胞的自身抗原可调控中枢神经系统的免疫耐受。实验设计：为评估少突胶质细胞Ecm29条件性敲除（cKO）对中枢神经系统实质组织内促炎应答的影响，本研究对受EAE影响的脊髓与脑组织开展了转录组分析，并对从少突胶质细胞Ecm29 cKO小鼠中分离得到的O4+少突胶质细胞/施万细胞开展了比较基因表达谱RNA测序（RNA Sequencing, RNA-seq）分析。