Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice
Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice
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DOI：
10.1073/pnas.0802644105
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发表时间：
2008-04-29
影响因子：
11.1
通讯作者：
DiLorenzo, Teresa P.
中科院分区：
文献类型：
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作者：
Mukhopadhaya, Arunika;Hanafusa, Tadashi;DiLorenzo, Teresa P.
1 型糖尿病 (T1D) 是一种由中枢和外周耐受缺陷引起的自身免疫性疾病，其特征是 T 细胞介导的胰岛 β 细胞破坏。在NOD小鼠模型中，细胞毒性CD8+T细胞对β细胞抗原有反应，是T1D发展所必需的，并且在T1D患者的外周血中可以检测到对β细胞抗原具有特异性的CD8+T细胞。很明显，在非自身免疫倾向的小鼠中，树突状细胞 (DC) 在稳定状态下以耐受性方式呈递模型抗原，例如在没有感染的情况下，并导致 T 细胞最初增殖，但随后被删除或变得无反应。然而，这一基本概念尚未在自发性自身免疫性疾病的情况下进行评估。为此，我们通过内吞受体 DEC-205 将一种可被致糖尿病 CD8+ T 细胞克隆 A14 识别的模拟表位肽递送至 NOD 小鼠的 DC。最初观察到转移的抗原特异性 T 细胞的增殖，但随后被删除。获得耐受性是因为用佐剂中的模拟表位肽再次攻击小鼠不会诱导免疫反应。因此，即使在具有已知耐受缺陷的 NOD 小鼠中正在进行自身免疫的情况下，用 P 细胞抗原靶向 DC 也会导致自身反应性 CD8+ T 细胞的缺失。我们的结果为开发 DC 靶向自身抗原以治疗慢性 T 细胞介导的自身免疫性疾病提供了支持。
Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet beta cells. Cytotoxic CD8(+) T cells, reactive to beta cell antigens, are required for T1D development in the NOD mouse model of the disease, and CD8(+) T cells specific for beta cell antigens can be detected in the peripheral blood of T1D patients. It has been evident that in nonautoimmune-prone mice, dendritic cells (DCs) present model antigens in a tolerogenic manner in the steady state, e.g., in the absence of infection, and cause T cells to proliferate initially but then to be deleted or rendered unresponsive. However, this fundamental concept has not been evaluated in the setting of a spontaneous autoimmune disease. To do so, we delivered a mimotope peptide, recognized by the diabetogenic CD8(+) T cell clone A14 to DCs in NOD mice via the endocytic receptor DEC-205. Proliferation of transferred antigen-specific T cells was initially observed, but this was followed by deletion. Tolerance was achieved because rechallenge of mice with the mimotope peptide in adjuvant did not induce an immune response. Thus, targeting of DCs with P cell antigens leads to deletion of autoreactive CD8+ T cells even in the context of ongoing autoimmunity in NOD mice with known tolerance defects. Our results provide support for the development of DC targeting of self antigens for treatment of chronic T cell-mediated autoimmune diseases.