Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
J Immunol. 2014 Jan 15;192(2):658-65. doi: 10.4049/jimmunol.1301904. Epub 2013 Dec 11.
Dendritic cells (DCs) are important orchestrators of the immune response, ensuring that immunity against pathogens is generated, whereas immunity against healthy tissues is prevented. Using the tumor Ag MUC1, we previously showed that i.v. immunization of MUC1 transgenic mice, but not wild-type, with a MUC1 peptide resulted in transient tolerization of all splenic DCs. These DCs did not upregulate costimulatory molecules and induced regulatory T cells rather than effector T cells. They were characterized by suppressed expression of a cohort of pancreatic enzymes not previously reported in DCs, which were upregulated in DCs presenting the same MUC1 peptide as a foreign Ag. In this article, we examined the self-antigen-tolerized DC phenotype, function, and mechanisms responsible for inducing or maintaining their tolerized state. Tolerized DCs share some characteristics with immature DCs, such as a less inflammatory cytokine/chemokine profile, deficient activation of NF-κB, and sustained expression of zDC and CCR2. However, tolerized DCs demonstrated a novel inducible expression of aldehyde dehydrogenase 1/2 and phospho-STAT3. Suppressed expression of one of the pancreatic enzymes, trypsin, in these DC impeded their ability to degrade extracellular matrix, thus affecting their motility. Suppressed metallopeptidases, reflected in low expression of carboxypeptidase B1, prevented optimal Ag-specific CD4(+) T cell proliferation suggesting their role in Ag processing. Tolerized DCs were not refractory to maturation after stimulation with a TLR3 agonist, demonstrating that this tolerized state is not terminally differentiated and that tolerized DCs can recover their ability to induce immunity to foreign Ags.
树突状细胞 (DCs) 是免疫反应的重要协调者，确保针对病原体的免疫得以产生，同时防止针对健康组织的免疫。我们之前使用肿瘤抗原 MUC1 表明，静脉内免疫接种 MUC1 转基因小鼠，但不是野生型，用 MUC1 肽可导致所有脾 DCs 的短暂耐受。这些 DC 没有上调共刺激分子，而是诱导调节性 T 细胞而不是效应 T 细胞。它们的特征是一组以前未在 DC 中报道过的胰腺酶表达受到抑制，而在呈递与作为外源 Ag 的相同 MUC1 肽的 DC 中上调。在本文中，我们研究了自身抗原耐受的 DC 表型、功能和诱导或维持其耐受状态的机制。耐受的 DC 与未成熟的 DC 具有一些共同特征，例如炎症细胞因子/趋化因子谱减少、NF-κB 激活缺陷和 zDC 和 CCR2 的持续表达。然而，耐受的 DC 表现出醛脱氢酶 1/2 和磷酸化 STAT3 的新诱导表达。这些 DC 中一种胰腺酶，即胰蛋白酶的表达受到抑制，会阻碍其降解细胞外基质的能力，从而影响其迁移能力。金属肽酶的表达受到抑制，反映为羧肽酶 B1 的低表达，会阻止最佳的 Ag 特异性 CD4(+)T 细胞增殖，表明其在 Ag 处理中的作用。在 TLR3 激动剂刺激后，耐受的 DC 不会对成熟产生抗性，这表明这种耐受状态不是终末分化的，并且耐受的 DC 可以恢复诱导对外国 Ag 的免疫的能力。
