Kiniry B E, Ganesh A, Critchfield J W, Hunt P W, Hecht F M, Somsouk M, Deeks S G, Shacklett B L
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, California, USA.
Division of Experimental Medicine, San Francisco General Hospital, San Francisco, California, USA.
Mucosal Immunol. 2017 Jul;10(4):1008-1020. doi: 10.1038/mi.2016.100. Epub 2016 Nov 9.
The gastrointestinal mucosa is an important site of HIV acquisition, viral replication, and pathogenesis. Immune cells in mucosal tissues frequently differ in phenotype and function from their non-mucosal counterparts. Although perforin-mediated cytotoxicity as measured in blood is a recognized correlate of HIV immune control, its role in gastrointestinal tissues is unknown. We sought to elucidate the cytotoxic features of rectal mucosal CD8 T-cells in HIV infected and uninfected subjects. Perforin expression and lytic capacity were significantly reduced in rectal CD8 T-cells compared with their blood counterparts, regardless of HIV clinical status; granzyme B (GrzB) was reduced to a lesser extent. Mucosal perforin and GrzB expression were higher in participants not on antiretroviral therapy compared with those on therapy and controls. Reduction in perforin and GrzB was not explained by differences in memory/effector subsets. Expression of T-bet and Eomesodermin was significantly lower in gut CD8 T-cells compared with blood, and in vitro neutralization of TGF-β partially restored perforin expression in gut CD8 T-cells. These findings suggest that rectal CD8 T-cells are primarily non-cytotoxic, and phenotypically shaped by the tissue microenvironment. Further elucidation of rectal immune responses to HIV will inform the development of vaccines and immunotherapies targeted to mucosal tissues.
胃肠道黏膜是HIV感染、病毒复制及发病机制的重要部位。黏膜组织中的免疫细胞在表型和功能上常常与其非黏膜对应细胞不同。尽管血液中检测到的穿孔素介导的细胞毒性是公认的HIV免疫控制的一个相关指标，但其在胃肠道组织中的作用尚不清楚。我们试图阐明HIV感染和未感染受试者直肠黏膜CD8 T细胞的细胞毒性特征。无论HIV临床状态如何，与血液中的对应细胞相比，直肠CD8 T细胞中的穿孔素表达和裂解能力均显著降低；颗粒酶B（GrzB）的降低程度较小。与接受抗逆转录病毒治疗的参与者和对照组相比，未接受抗逆转录病毒治疗的参与者黏膜穿孔素和GrzB表达更高。穿孔素和GrzB的降低不能用记忆/效应子亚群的差异来解释。与血液中的CD8 T细胞相比，肠道CD8 T细胞中T-bet和Eomesodermin的表达显著降低，体外中和转化生长因子-β可部分恢复肠道CD8 T细胞中穿孔素的表达。这些发现表明，直肠CD8 T细胞主要无细胞毒性，其表型由组织微环境塑造。进一步阐明直肠对HIV的免疫反应将为针对黏膜组织的疫苗和免疫疗法的开发提供依据。
