肝内交叉呈递和肝细胞抗原呈递在HBV特异性CD8 + T细胞应答的

StephenW

J Virol. 2018 Aug 8. pii: JVI.00920-18. doi: 10.1128/JVI.00920-18. [Epub ahead of print]
Intrahepatic Cross-Presentation and Hepatocellular Antigen Presentation Play Distinct Roles in the Induction of HBV-Specific CD8+ T Cell Responses.
Murata Y1,2, Kawashima K3,4, Sheikh K1, Tanaka Y3, Isogawa M5,3.
Author information
Abstract

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 MHC class I expression was mostly restricted to non-hematopoietic 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.IMPORTANCE 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.

PMID:
    30089700
DOI:
    10.1128/JVI.00920-18

StephenW

J Virol。 2018年8月8日.pii：JVI.00920-18。 doi：10.1128 / JVI.00920-18。 [提前打印]
肝内交叉呈递和肝细胞抗原呈递在HBV特异性CD8 + T细胞应答的诱导中发挥不同的作用。
Murata Y1,2，Kawashima K3,4，Sheikh K1，Tanaka Y3，Isogawa M5,3。
作者信息
抽象

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物。然而，围绕引发HBV特异性CD8 + T细胞反应的早期免疫事件仍然知之甚少。本研究利用急性和慢性HBV感染的动物模型检测了引发定位的重要性以及肝细胞内源性抗原呈递与骨髓衍生细胞交叉呈递对诱导功能性HBV特异性CD8 + T细胞应答的相对贡献的重要性。 。功能性HBV特异性CD8 + T细胞应答可诱导至肝内表达的HBV，即使T细胞归巢至淋巴组织被严重抑制，表明功能性引发可能发生在肝脏中。在MHC I类表达主要限于非造血细胞的小鼠中，HBV特异性CD8 + T细胞的扩增显着减少，这表明造血细胞交叉呈递在HBV特异性CD8 + T细胞诱导中的重要性。引人注目的是，在MHC I类表达限于造血细胞的小鼠中，HBV特异性CD8 + T细胞的扩增和细胞溶解分化甚至更严重地降低。总的来说，这些结果表明需要交叉呈递，但就诱导HBV特异性CD8 + T细胞的细胞溶解作用而言相对低效。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。重要性乙型肝炎病毒（HBV）引起急性和慢性肝炎。大约有2.6亿人长期感染HBV，并且患上肝硬化和肝细胞癌的风险增加。宿主免疫应答，特别是HBV特异性CD8 + T细胞应答，在很大程度上决定了HBV感染的结果。广泛接受的是抗原缺乏经验的CD8 + T细胞应该首先被淋巴组织中的专职抗原呈递细胞（pAPC）激活以分化成效应CD8 + T细胞。然而，这一概念尚未针对HBV特异性CD8 + T细胞进行测试。在本研究中，我们显示可以在肝脏中诱导HBV特异性CD8 + T细胞应答。令人惊讶的是，肝细胞的抗原呈递比造血细胞的交叉呈递更重要，用于诱导HBV特异性CD8 + T细胞应答。这些结果揭示了肝细胞在诱导HBV特异性CD8 + T细胞应答中抗原呈递的先前未被认识的作用。

结论：
    30089700
DOI：
    10.1128 / JVI.00920-18