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.蛋白酶体（Proteasomes）催化蛋白质降解，产生呈递于细胞表面的抗原肽——这一过程在神经胶质细胞（Neuroglia，即少突胶质细胞Oligodendrocytes与小胶质细胞Microglia）中可对外界刺激产生高度响应。然而，中枢神经系统（Central Nervous System, CNS）实质细胞所呈递的自身抗原功能仍未明确。本研究证实，神经胶质细胞源性自身抗原的保真度，可通过上调调节性T细胞（Regulatory T cell, Treg）群体数量，抑制致脑炎性T细胞应答。我们证明，蛋白酶体衔接蛋白Ecm29的缺失，会改变神经元与神经胶质细胞表面呈递抗原的效率与精准度。诱导性少突胶质细胞或小胶质细胞特异性Ecm29条件性敲除（conditional knockout, cKO）小鼠的实验性自身免疫性脑脊髓炎（Experimental Autoimmune Encephalomyelitis, EAE）症状较野生型小鼠更为严重，同时其脊髓内调节性T细胞数量减少。MHC-I H2-Db免疫肽组谱分析发现，存在可调节髓鞘反应性T细胞增殖与细胞毒性的自身抗原。通过脊髓内腺相关病毒（Adeno-associated virus, AAV）/Olig001介导的自身抗原NDUFA1p在新生小鼠体内的表达，可有效缓解实验性自身免疫性脑脊髓炎，并增加识别NDUFA1p-H2Db复合物的CD103+CD8+CD122+调节性T细胞数量。综上，由Ecm29/蛋白酶体调控、神经胶质细胞来源的自身抗原，可调节中枢神经系统的免疫耐受。