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HLA-E-restricted CD8+ T Lymphocytes Efficiently Control Mycobacterium tuberculosis and HIV-1 Coinfection.

HLA-E 限制性 CD8 + T 淋巴细胞有效控制结核分枝杆菌和 HIV-1 共感染。

  • 影响因子:3.37
  • DOI:10.1165/rcmb.2019-0261OC
  • 作者列表:"La Manna MP","Orlando V","Prezzemolo T","Di Carlo P","Cascio A","Delogu G","Poli G","Sullivan LC","Brooks AG","Dieli F","Caccamo N
  • 发表时间:2020-04-01
Abstract

We investigated the contribution of human leukocyte antigen A2 (HLA-A2) and HLA-E-restricted CD8+ T cells in patients with Mycobacterium tuberculosis and human immunodeficiency virus 1 (HIV-1) coinfection. HIV-1 downregulates HLA-A, -B, and -C molecules in infected cells, thus influencing recognition by HLA class I-restricted CD8+ T cells but not by HLA-E-restricted CD8+ T cells, owing to the inability of the virus to downmodulate their expression. Therefore, antigen-specific HLA-E-restricted CD8+ T cells could play a protective role in Mycobacterium tuberculosis and HIV-1 coinfection. HLA-E- and HLA-A2-restricted Mycobacterium tuberculosis-specific CD8+ T cells were tested in vitro for cytotoxic and microbicidal activities, and their frequencies and phenotypes were evaluated ex vivo in patients with active tuberculosis and concomitant HIV-1 infection. HIV-1 and Mycobacterium tuberculosis coinfection caused downmodulation of HLA-A2 expression in human monocyte-derived macrophages associated with resistance to lysis by HLA-A2-restricted CD8+ T cells and failure to restrict the growth of intracellular Mycobacterium tuberculosis. Conversely, HLA-E surface expression and HLA-E-restricted cytolytic and microbicidal CD8 responses were not affected. HLA-E-restricted and Mycobacterium tuberculosis-specific CD8+ T cells were expanded in the circulation of patients with Mycobacterium tuberculosis/HIV-1 coinfection, as measured by tetramer staining, but displayed a terminally differentiated and exhausted phenotype that was rescued in vitro by anti-PD-1 (programmed cell death protein 1) monoclonal antibody. Together, these results indicate that HLA-E-restricted and Mycobacterium tuberculosis-specific CD8+ T cells in patients with Mycobacterium tuberculosis/HIV-1 coinfection have an exhausted phenotype and fail to expand in vitro in response to antigen stimulation, which can be restored by blocking the PD-1 pathway using the specific monoclonal antibody nivolumab.

摘要

我们研究了人类白细胞抗原 A2 (HLA-A2) 和 HLA-E 限制性 CD8 + T 细胞在结核分枝杆菌和人类免疫缺陷病病毒 HIV-1) 共感染患者中的作用。HIV-1 下调感染细胞中的 HLA-A 、-B 和-C 分子,因此,由于病毒无法下调其表达,影响 HLA I 类限制性 CD8 + T 细胞的识别,而不影响 HLA-E 限制性 CD8 + T 细胞的识别。因此,抗原特异性 HLA-E 限制性 CD8 + T 细胞可在结核分枝杆菌和 HIV-1 共感染中发挥保护作用。体外检测 HLA-E 和 HLA-A2-restricted 结核分枝杆菌特异性 CD8 + T 细胞的细胞毒性和杀微生物活性,并在活动性结核合并 HIV-1 感染患者中进行了体外频率和表型评估。HIV-1 和结核分枝杆菌共感染引起人单核细胞来源的巨噬细胞 HLA-A2 表达下调,与 HLA-A2-restricted CD8 + T 细胞裂解相关,未能限制细胞内结核分枝杆菌的生长。相反,HLA-E 表面表达和 HLA-E 限制性溶细胞和杀微生物 CD8 反应不受影响。通过四聚体染色测定,HLA-E 限制性和结核分枝杆菌特异性 CD8 + T 细胞在结核分枝杆菌/HIV-1 共感染患者的循环中扩增,但表现出终末分化和耗竭的表型,在体外被 anti-PD-1 (程序性细胞死亡蛋白 1) 单克隆抗体拯救。一起,这些结果表明,结核分枝杆菌/HIV-1 共感染患者的 HLA-E 限制性和结核分枝杆菌特异性 CD8 + T 细胞具有耗竭的表型,并且不能在体外响应抗原扩增。刺激,其可以通过使用特异性单克隆抗体 nivolumab 阻断 PD-1 通路来恢复。

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