Shoukry Naglaa H, Grakoui Arash, Houghton Michael, Chien David Y, Ghrayeb John, Reimann Keith A, Walker Christopher M
Center for Vaccines and Immunity, Columbus Children's Research Institute, Columbus, OH 43205, USA.
J Exp Med. 2003 Jun 16;197(12):1645-55. doi: 10.1084/jem.20030239.
Few hepatitis C virus (HCV) infections resolve spontaneously but those that do appear to afford protective immunity. Second infections are usually shorter in duration and are less likely to persist but mechanisms of virus control in immune individuals have not been identified. In this study we investigated whether memory helper and/or cytotoxic T lymphocytes provide protection in chimpanzees serially reinfected with the virus. Clearance of the first infection took 3-4 mo and coincided with the delayed onset of CD4+ and CD8+ T cell responses. High frequencies of memory T cells targeting multiple HCV proteins were stable over 7 yr of follow-up. Animals were infected for a second time to assess the protective role of memory T cells. In contrast to the prolonged course of the first infection, viremia was terminated within 14 d. Control of this second infection was kinetically linked to rapid acquisition of virus-specific cytolytic activity by liver resident CD8+ T cells and expansion of memory CD4+ and CD8+ T cells in blood. The importance of memory CD8+ T cells in control of HCV infection was confirmed by antibody-mediated depletion of this lymphocyte subset before a third infection. Virus replication was prolonged despite the presence of memory CD4+ T helper cells primed by the two prior infections and was not terminated until HCV-specific CD8+ T cells recovered in the liver. These experiments demonstrate an essential role for memory CD8+ T cells in long-term protection from chronic hepatitis C.
很少有丙型肝炎病毒（HCV）感染能自发清除，但那些能自发清除的感染似乎能提供保护性免疫。再次感染时病程通常较短，持续存在的可能性也较小，但免疫个体中病毒控制的机制尚未明确。在本研究中，我们调查了记忆辅助性T淋巴细胞和/或细胞毒性T淋巴细胞在被该病毒连续感染的黑猩猩中是否提供保护作用。首次感染的清除需要3 - 4个月，同时伴有CD4⁺和CD8⁺T细胞反应的延迟出现。针对多种HCV蛋白的记忆T细胞高频率在7年的随访中保持稳定。动物再次感染以评估记忆T细胞的保护作用。与首次感染的漫长病程不同，病毒血症在14天内就被清除。第二次感染的控制在动力学上与肝脏驻留CD8⁺T细胞快速获得病毒特异性细胞溶解活性以及血液中记忆CD4⁺和CD8⁺T细胞的扩增相关。在第三次感染前通过抗体介导清除该淋巴细胞亚群，证实了记忆CD8⁺T细胞在控制HCV感染中的重要性。尽管存在由前两次感染激活的记忆CD4⁺辅助性T细胞，病毒复制仍持续延长，直到肝脏中HCV特异性CD8⁺T细胞恢复，病毒复制才停止。这些实验证明了记忆CD8⁺T细胞在长期预防慢性丙型肝炎中起着至关重要的作用。
