HLA-E-restricted CD8+ T Lymphocytes Efficiently Control Mycobacterium tuberculosis and HIV-1 Coinfection
HLA-E-restricted CD8+ T Lymphocytes Efficiently Control Mycobacterium tuberculosis and HIV-1 Coinfection
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DOI：
10.1165/rcmb.2019-0261oc
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发表时间：
2020-04-01
影响因子：
6.4
通讯作者：
Caccamo, Nadia
中科院分区：
文献类型：
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作者：
La Manna, Marco Pio;Orlando, Valentina;Caccamo, Nadia
我们研究了人白细胞抗原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毒1 （HIV-1）合并感染患者中的作用。HIV-1下调感染细胞中的HLA- a、-B和-C分子，从而影响HLA- i类限制性CD8(+) T细胞的识别，而HLA- e类限制性CD8(+) T细胞的识别，这是由于病毒无法下调这些分子的表达。因此，抗原特异性hlae限制性CD8(+) T细胞可能在结核分枝杆菌和HIV-1合并感染中发挥保护作用。在体外测试了HLA-E-和hla - a2限制性结核分枝杆菌特异性CD8(+) T细胞的细胞毒和杀微生物活性，并评估了活动性结核病合并HIV-1感染患者体内CD8(+) T细胞的频率和表型。HIV-1和结核分枝杆菌的共同感染导致人单核细胞源性巨噬细胞中HLA-A2表达下调，这与HLA-A2限制性CD8(+) T细胞的裂解抵抗和细胞内结核分枝杆菌的生长失败有关。相反，HLA-E表面表达和HLA-E限制性c细胞溶解和杀微生物CD8反应不受影响。通过四聚体染色检测，在结核分枝杆菌/HIV-1合并感染患者的循环中，hla - e限制性和结核分枝杆菌特异性CD8(+) T细胞扩增，但在体外通过抗pd -1（程序性细胞死亡蛋白1）单克隆抗体挽救，显示出终末分化和耗尽的表型。总之，这些结果表明，在结核分枝杆菌/HIV-1合并感染患者中，hla - e限制性和结核分枝杆菌特异性CD8(+) T细胞具有耗尽表型，并且在抗原刺激下不能在体外扩增，可以通过使用特异性单克隆抗体nivolumab阻断PD-1途径来恢复。
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 HLAE-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 c ytolytic 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.