Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Institute of Immunology, University of Science and Technology of China, Hefei, China.
Front Immunol. 2022 Sep 20;13:993246. doi: 10.3389/fimmu.2022.993246. eCollection 2022.
It was extensively recognized that central tolerance to HBV exists in HBs-transgenic (Tg) mice, however, the immune response to HBV vaccine may be inspired in adult HBs-Tg mice after boosting with potent adjuvants, leaving a mystery to explore its immune tolerance. Here, WT-HBs-Tg parabiotic mice model was generated by conjoining WT (donor) and HBs-Tg (host) mouse parabiotic surgery, in order to see how immunocompetent WT mice naturally respond to HBV, and how tolerant HBs-Tg mice influence the anti-HBV immunity from WT mice. It was found that WT CD8 T cells markedly accumulated into the liver of HBs-Tg parabionts, and importantly, almost all HBsAg-specific CD8 T cells derived from WT but not HBs-Tg mice, making a clear separation of a normal immune response from WT donor and a tolerant response by recipient host. Further, in the absence of host but not donor spleen, HBsAg-specific CD8 T cells disappeared, indicating that host spleen was the indispensable site for donor HBsAg-specific CD8 T cell priming though its mechanisms need further study. We found that donor CD4 T helper cells were necessary for donor HBsAg-specific CD8 T cell response by CD4-deficiency in WT or in HBs-Tg mice, indicating that an immune response was elicited between CD4 T helper cells and CD8 cytotoxic T cells of donor in the host but not donor spleen. It was noted that compared to donor CD4 T cells, host CD4 T cells were characterized with more tolerant features by harboring more CD25Foxp3 Tregs with higher expression of PD-1 and TIGIT in the spleen of HBs-Tg parabionts, which exhibited suppressive function on CD8 T cells directly. Moreover, the Th1/Treg ratio was enhanced after parabiosis, suggesting that donor T helper cells may overcome the negative regulation of host Tregs in host spleen. In conclusion, both incompetent anti-HBV CD8 T cells and insufficient help from CD4 T cells are the major mechanisms underlying immune tolerance in HBs-Tg mice which helps explain HBV persistence.
人们广泛认识到，HBV 转基因（Tg）小鼠存在中枢耐受，但在使用强效佐剂增强后，成年 HBs-Tg 小鼠对 HBV 疫苗可能会产生免疫反应，这留下了一个谜团，有待探索其免疫耐受机制。在这里，通过将 WT（供体）和 HBs-Tg（宿主）小鼠联体手术，生成了 WT-HBs-Tg 联体小鼠模型，以观察免疫功能正常的 WT 小鼠如何自然地对 HBV 产生反应，以及 HBs-Tg 小鼠的免疫耐受如何影响来自 WT 小鼠的抗 HBV 免疫。结果发现，WT CD8 T 细胞明显聚集到 HBs-Tg 联体小鼠的肝脏中，重要的是，几乎所有 HBsAg 特异性 CD8 T 细胞都来自 WT 而不是 HBs-Tg 小鼠，从而清楚地区分了来自 WT 供体的正常免疫反应和受体宿主的耐受反应。此外，在没有宿主但有供体脾脏的情况下，HBsAg 特异性 CD8 T 细胞消失，表明宿主脾脏是供体 HBsAg 特异性 CD8 T 细胞启动的不可或缺部位，但其机制仍需进一步研究。我们发现，通过在 WT 或 HBs-Tg 小鼠中缺乏 CD4 缺陷，供体 CD4 T 辅助细胞是供体 HBsAg 特异性 CD8 T 细胞反应所必需的，这表明在宿主中，而不是在供体脾脏中，供体 CD4 T 辅助细胞与 CD8 细胞毒性 T 细胞之间引发了免疫反应。值得注意的是，与供体 CD4 T 细胞相比，宿主 CD4 T 细胞在 HBs-Tg 联体小鼠的脾脏中具有更多的耐受特征，表现为更多表达 PD-1 和 TIGIT 的 CD25Foxp3 Treg，并具有直接抑制 CD8 T 细胞的功能。此外，联体后 Th1/Treg 比值增强，表明供体辅助性 T 细胞可能克服了宿主脾脏中宿主 Treg 的负调节。总之，无能的抗 HBV CD8 T 细胞和来自 CD4 T 细胞的不足帮助解释了 HBs-Tg 小鼠的免疫耐受机制，有助于解释 HBV 的持续存在。
