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Targeting of antigens to B cells augments antigen-specific T-cell responses and breaks immune tolerance to tumor-associated antigen MUC1

机译:将抗原靶向B细胞可增强抗原特异性T细胞应答并破坏对肿瘤相关抗原MUC1的免疫耐受

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摘要

B cells are antibody (Ab)–secreting cells as well as potent antigen (Ag)–presenting cells that prime T-cell activation, which evokes great interest in their use for vaccine development. Here, we targeted ovalbumin (OVA) to B cells via CD19 and found that a single low dose of anti–CD19-OVA conjugates, but not isotype mAb-OVA, stimulated augmented CD4 and CD8 T-cell proliferation and expansion. Administration of TLR9 agonist CpG could significantly enhance long-term T-cell survival. Similar results were obtained when the tumor-associated Ag MUC1 was delivered to B cells. MUC1 transgenic (Tg) mice were previously found to lack effective T-cell help and produce low-titer of anti-MUC1 Abs after vaccination. Targeting MUC1 to B cells elicited high titer of anti-MUC1 Abs with different isotypes, predominantly IgG2a and IgG2b, in MUC1 Tg mice. The isotype switching of anti-MUC1 Ab was CD4 dependent. In addition, IFN-γ–producing CD8 T cells and in vivo cytolytic activity were significantly increased in these mice. The mice also showed significant resistance to MUC1+ lymphoma cell challenge both in the prophylactic and therapeutic settings. We conclude that Ags targeting to B cells stimulate CD4 and CD8 T-cell responses as well as Th-dependent humoral immune responses.
机译:B细胞既是分泌抗体(Ab)的细胞,又是有效抗原(Ag)的细胞,这些细胞引发T细胞活化,这引起了人们对其疫苗开发应用的极大兴趣。在这里,我们通过CD19将卵清蛋白(OVA)靶向B细胞,发现单个低剂量的抗CD19-OVA缀合物(而不是同型mAb-OVA)刺激CD4和CD8 T细胞增殖和扩增。使用TLR9激动剂CpG可以显着提高长期T细胞存活率。当肿瘤相关的Ag MUC1被递送至B细胞时,获得了相似的结果。以前发现MUC1转基因(Tg)小鼠缺乏有效的T细胞帮助,接种疫苗后产生的抗MUC1 Abs抗体滴度较低。将MUC1靶向B细胞可在MUC1 Tg小鼠中引起高滴度的不同同种型抗MUC1 Abs,主要是IgG2a和IgG2b。抗MUC1 Ab的同种型转换是CD4依赖的。此外,这些小鼠中产生IFN-γ的CD8 T细胞和体内溶细胞活性显着增加。小鼠在预防和治疗方面均显示出对MUC1 +淋巴瘤细胞攻击的显着抵抗力。我们得出结论,针对B细胞的Ags刺激CD4和CD8 T细胞反应以及Th依赖的体液免疫反应。

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