Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
J Virol. 2018 Oct 12;92(21). doi: 10.1128/JVI.00920-18. Print 2018 Nov 1.
CD8 T cells are the key cellular effectors mediating the clearance of hepatitis B virus (HBV) infections. However, early immunological events surrounding the priming of HBV-specific CD8 T cell responses remain poorly understood. This study examined the importance of priming location and the relative contribution of endogenous antigen presentation by hepatocytes versus cross-presentation by bone marrow-derived cells to the induction of functional HBV-specific CD8 T cell responses using the animal models of acute and chronic HBV infection. Functional HBV-specific CD8 T cell responses could be induced to intrahepatically expressed HBV even when T cell homing to the lymphoid tissues was severely suppressed, suggesting that functional priming could occur in the liver. The expansion of HBV-specific CD8 T cells was significantly reduced in the mice whose major histocompatibility complex (MHC) class I expression was mostly restricted to nonhematopoietic cells, suggesting the importance of cross-presentation by hematopoietic cells in the induction of HBV-specific CD8 T cells. Strikingly, the expansion and cytolytic differentiation of HBV-specific CD8 T cells were reduced even more severely in the mice whose MHC class I expression was restricted to hematopoietic cells. Collectively, these results indicate that cross-presentation is required but relatively inefficient in terms of inducing the cytolytic differentiation of HBV-specific CD8 T cells by itself. Instead, the expansion and functional differentiation of HBV-specific CD8 T cells are primarily dependent on hepatocellular antigen presentation. Hepatitis B virus (HBV) causes acute and chronic hepatitis. Approximately 260 million people are chronically infected with HBV and under an increased risk of developing cirrhosis and hepatocellular carcinoma. Host immune responses, particularly HBV-specific CD8 T cell responses, largely determine the outcome of HBV infection. It is widely accepted that antigen inexperienced CD8 T cells should be initially activated by professional antigen-presenting cells (pAPCs) in lymphoid tissues to differentiate into effector CD8 T cells. However, this notion has not been tested for HBV-specific CD8 T cells. In this study, we show that HBV-specific CD8 T cell responses can be induced in the liver. Surprisingly, antigen presentation by hepatocytes is more important than cross-presentation by hematopoietic cells for the induction of HBV-specific CD8 T cell responses. These results revealed a previously unappreciated role of antigen presentation by hepatocytes in the induction of HBV-specific CD8 T cell responses.
CD8 T 细胞是介导乙型肝炎病毒 (HBV) 感染清除的关键细胞效应因子。然而，HBV 特异性 CD8 T 细胞反应的初始免疫事件仍知之甚少。本研究使用急性和慢性 HBV 感染的动物模型，研究了初始位置的重要性以及肝细胞内源性抗原呈递与骨髓来源细胞交叉呈递对功能性 HBV 特异性 CD8 T 细胞反应诱导的相对贡献。即使 T 细胞归巢到淋巴组织受到严重抑制，也可以诱导在肝内表达的 HBV 的功能性 HBV 特异性 CD8 T 细胞反应，这表明功能性初始可以在肝脏中发生。在 MHC Ⅰ类表达主要局限于非造血细胞的小鼠中，HBV 特异性 CD8 T 细胞的扩增显著减少，这表明造血细胞的交叉呈递在诱导 HBV 特异性 CD8 T 细胞中的重要性。引人注目的是，在 MHC Ⅰ类表达仅限于造血细胞的小鼠中，HBV 特异性 CD8 T 细胞的扩增和细胞毒性分化受到更严重的限制。总之，这些结果表明，尽管交叉呈递本身在诱导 HBV 特异性 CD8 T 细胞的细胞毒性分化方面是必需的，但效率相对较低。相反，HBV 特异性 CD8 T 细胞的扩增和功能分化主要依赖于肝细胞抗原呈递。乙型肝炎病毒 (HBV) 可引起急性和慢性肝炎。大约有 2.6 亿人慢性感染 HBV，患肝硬化和肝细胞癌的风险增加。宿主免疫反应，特别是 HBV 特异性 CD8 T 细胞反应，在很大程度上决定了 HBV 感染的结果。广泛接受的观点是，抗原未经验的 CD8 T 细胞最初应通过淋巴组织中的专业抗原呈递细胞 (pAPC) 激活，以分化为效应 CD8 T 细胞。然而，这一概念尚未在 HBV 特异性 CD8 T 细胞中得到验证。在这项研究中，我们表明可以在肝脏中诱导 HBV 特异性 CD8 T 细胞反应。令人惊讶的是，与造血细胞的交叉呈递相比，肝细胞的抗原呈递对诱导 HBV 特异性 CD8 T 细胞反应更为重要。这些结果揭示了肝细胞在诱导 HBV 特异性 CD8 T 细胞反应中的先前未被认识到的作用。
