Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada.
Pharmazentrum Frankfurt, Klinikum der Goethe Universität Frankfurt, Frankfurt, Germany.
J Clin Invest. 2020 Apr 1;130(4):1823-1829. doi: 10.1172/JCI130670.
Peptide MHC class II-based (pMHCII-based) nanomedicines trigger the formation of multicellular regulatory networks by reprogramming autoantigen-experienced CD4+ T cells into autoimmune disease-suppressing T regulatory type 1 (TR1) cells. We have shown that pMHCII-based nanomedicines displaying liver autoimmune disease-relevant yet ubiquitously expressed antigens can blunt various liver autoimmune disorders in a non-disease-specific manner without suppressing local or systemic immunity against infectious agents or cancer. Here, we show that such ubiquitous autoantigen-specific T cells are also awakened by extrahepatic tissue damage and that the corresponding TR1 progeny can suppress experimental autoimmune encephalomyelitis (EAE) and pancreatic β cell autoreactivity. In mice having EAE, nanomedicines displaying either ubiquitous or CNS-specific epitopes triggered the formation and expansion of cognate TR1 cells and their recruitment to the CNS-draining lymph nodes, sparing their liver-draining counterparts. Surprisingly, in mice having both liver autoimmunity and EAE, liver inflammation sequestered these ubiquitous or even CNS-specific TR1 cells away from the CNS, abrogating their antiencephalitogenic activity. In these mice, only the ubiquitous antigen-specific TR1 cells suppressed liver autoimmunity. Thus, the scope of antigen spreading in autoimmune disorders is larger than previously anticipated, involving specificities expected to be silenced by mechanisms of tolerance; the regulatory activity, but not the retention of autoreactive TR1 cells, requires local autoantigen expression.
基于多肽 MHC II 类（pMHCII 类）的纳米药物通过将自身抗原经验的 CD4+T 细胞重新编程为自身免疫疾病抑制性 T 调节型 1（TR1）细胞，触发多细胞调节网络的形成。我们已经表明，展示肝脏自身免疫疾病相关但普遍表达的抗原的基于 pMHCII 的纳米药物可以以非疾病特异性方式减轻各种肝脏自身免疫疾病，而不会抑制针对感染原或癌症的局部或全身免疫。在这里，我们表明，这种普遍的自身抗原特异性 T 细胞也被肝外组织损伤所唤醒，相应的 TR1 后代可以抑制实验性自身免疫性脑脊髓炎（EAE）和胰腺β细胞自身反应性。在患有 EAE 的小鼠中，显示普遍或中枢神经系统特异性表位的纳米药物触发了同源 TR1 细胞的形成和扩增及其向中枢神经系统引流淋巴结的募集，而不会募集其肝引流的对应物。令人惊讶的是，在同时患有肝脏自身免疫和 EAE 的小鼠中，肝脏炎症将这些普遍存在的甚至中枢神经系统特异性的 TR1 细胞从中枢神经系统中隔离出来，从而消除了它们的抗脑炎活性。在这些小鼠中，只有普遍存在的抗原特异性 TR1 细胞抑制了肝脏自身免疫。因此，自身免疫性疾病中抗原扩散的范围比以前预期的要大，涉及预期被耐受机制沉默的特异性；调节活性，但不是自身反应性 TR1 细胞的保留，需要局部自身抗原表达。
