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.

中文翻译：

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遍在抗原特异性T调节型1细胞可变地抑制肝和肝外自身免疫。

基于肽MHC II类（基于pMHCII的）纳米药物通过将自身抗原经历的CD4 + T细胞重编程为自身免疫性疾病抑制性T调节性1型（TR1）细胞，从而触发了多细胞调节网络的形成。我们已经显示，基于pMHCII的纳米药物显示出与肝脏自身免疫性疾病相关但普遍表达的抗原，可以以非疾病特异性方式钝化各种肝脏自身免疫性疾病，而不会抑制针对感染因子或癌症的局部或全身性免疫。在这里，我们显示出这种普遍存在的自身抗原特异性T细胞也被肝外组织损伤唤醒，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，显示出普遍存在或中枢神经系统特异性表位的纳米药物触发了同源TR1细胞的形成和扩展，并将其募集至中枢神经系统引流淋巴结，从而节省了其肝脏引流对应物。出乎意料的是，在具有肝自身免疫和EAE的小鼠中，肝炎症使这些普遍存在的或什至是CNS特异性的TR1细胞与CNS隔离开来，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细胞抑制了肝自身免疫。因此，自身免疫性疾病中抗原传播的范围比以前预期的要大，涉及特异性可能被耐受机制沉默。调节活性而不是自身反应性TR1细胞的保留需要局部自身抗原表达。