Selective Upregulation of CTLA-4 on CD8+T Cells Restricted by HLA-B*35Px Renders them to an Exhausted Phenotype in HIV-1 infection
Selective Upregulation of CTLA-4 on CD8+T Cells Restricted by HLA-B*35Px Renders them to an Exhausted Phenotype in HIV-1 infection
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DOI：
10.1371/journal.ppat.1008696
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发表时间：
2020-08-01
期刊：
影响因子：
6.7
通讯作者：
Houston, Stan
中科院分区：
文献类型：
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作者：
Elahi, Shokrollah;Shahbaz, Shima;Houston, Stan
人类白细胞抗原B*35px与HIV-1疾病快速发展为艾滋病有关。然而，这种人类白细胞抗原等位基因对HIV-1感染结局产生有害影响的机制(S)还不完全清楚。CD8(+)T细胞在控制病毒复制方面起着至关重要的作用，但CD8(+)T细胞受损是HIV-1感染的主要标志。在此，我们检测了CD8(+)T细胞受人类白细胞抗原B*35px(人类白细胞抗原B*35：03和人类白细胞抗原B*35：02)、人类白细胞抗原B*27/B57和非人类白细胞抗原B*27/B57(如：人类白细胞抗原A*01、A*02、A*03、A*11、A*24、A*26、B*40、B*08、B*38、B*44)所限制的效应功能。与人类白细胞抗原B*27/B57和非人类白细胞抗原B*27/B57相比，人类白细胞抗原B*35px限制的CD8(+)T细胞的表型受损。CD8(+)T细胞受到非人类白细胞抗原B*27/B57同源表位的限制时，上调TIM-3，从而通过TIM-3：Galectin-9(Gal-9)被调节性T细胞(Tregs)抑制。值得注意的是，受HLAB*35px限制的CD8(+)T细胞表达的TIM-3较少，因此不受Tregs的抑制，这与受HLAB*27/B57限制的CD8(+)T细胞相似。相反，被人类白细胞抗原B*35px限制的CD8(+)T细胞在识别其同源表位时上调了CTLA-4。人类白细胞抗原B*35限制的HIV特异性CD8(+)T细胞的转录和表型受损(如效应功能低下)与持续的CTLA-4、升高的eome和blimp-1有关，但T-bet表达较低。因此，抗CTLA-4抗体伊匹单抗能逆转受HLA-B*35px限制的抗原特异性CD8(+)T细胞的增殖能力，但不能逆转其他因素。本研究支持CD8(+)T细胞对Tregs介导的抑制的抵抗力与等位基因限制有关，而不是与表位特异性有关。我们的结果有助于解释一种新的机制，即HIV特异性CD8(+)T细胞无法控制病毒的复制。作者摘要：一组罕见的携带HLA-B*35px的HIV感染者迅速进展为艾滋病，而携带HLA-B*27和HLA-B*57的HIV感染者则不会进展。以前的研究表明，病毒突变可能会阻止那些具有HLA-B*35px的人对病毒的强大免疫反应。然而，受人类白细胞抗原-B*35px限制的HIV特异性CD8(+)T细胞的功能仍不清楚。在这项研究中，我们证明了人类白细胞抗原-B*35px(HLA-B*35：03和HLA-B*35：02)限制的HIV特异性CD8(+)T细胞表现出一种受损的表型(如低增殖能力、低细胞毒分子表达和低细胞因子产生能力)。有趣的是，受人类白细胞抗原-B*27/B*57限制的CD8(+)T细胞逃避调节性T细胞(Tregs)的抑制，而不是由非人类白细胞抗原-B*27/B*57限制的T细胞。非HLA-B*27/B*57限制的CD8(+)T细胞在遇到其表位时上调TIM-3，但不受HLA-B*27/B*57和HLA-B*35px限制的CD8(+)T细胞。因此，受非人类白细胞抗原B*27/B*57限制的CD8(+)T细胞通过TIM-3：Galectin-9相互作用被Tregs抑制。值得注意的是，受HLA-B*35px限制的CD8(+)T细胞在遇到其表位时上调CTLA-4，导致其表型耗尽。这种差异反应与CD8(+)T细胞中EBES、Blimp-1的上调和T-bet的低表达有关，受HLA-B*35px的限制。这些结果表明，使用抗CTLA-4抗体使这些细胞恢复活力可能是可行的。
HLA-B*35Px is associated with HIV-1 disease rapid progression to AIDS. However, the mechanism(s) underlying this deleterious effect of this HLA allele on HIV-1 infection outcome has not fully understood. CD8(+)T cells play a crucial role to control the viral replication but impaired CD8(+)T cells represent a major hallmark of HIV-1 infection. Here, we examined the effector functions of CD8(+)T cells restricted by HLA-B*35Px (HLA-B*35:03 and HLA-B*35:02), HLA-B*27/B57 and non-HLA-B*27/B57 (e.g. HLA-A*01, A*02, A*03, A*11, A*24, A*26, B*40, B*08, B*38, B*44). CD8(+)T cells restricted by HLA-B*35Px exhibited an impaired phenotype compared with those restricted by HLA-B*27/B57 and even non-HLA-B*27/B57. CD8(+)T cells restricted by non-HLA-B*27/B57 when encountered their cognate epitopes upregulated TIM-3 and thus became suppressed by regulatory T cells (Tregs) via TIM-3: Galectin-9 (Gal-9). Strikingly, CD8(+)T cells restricted by HLA-B*35Px expressed fewer TIM-3 and therefore did not get suppressed by Tregs, which was similar to CD8(+)T cells restricted by HLA-B*27/B57. Instead, CD8(+)T cells restricted by HLA-B*35Px upon recognition of their cognate epitopes upregulated CTLA-4. The transcriptional and impaired phenotype (e.g. poor effector functions) of HIV-specific CD8(+)T cells restricted by HLA-B*35 was related to persistent CTLA-4, elevated Eomes and blimp-1 but poor T-bet expression. As such, anti-CTLA-4 antibody, Ipilimumab, reversed the impaired proliferative capacity of antigen-specific CD8(+)T cells restricted by HLA-B*35Px but not others. This study supports the concept that CD8(+)T resistance to Tregs-mediated suppression is related to allele restriction rather than the epitope specificity. Our results aid to explain a novel mechanism for the inability of HIV-specific CD8(+)T cells restricted by HLA-B*35Px to control viral replication.Author summary A rare group of HIV-infected individuals with HLA-B*35Px rapidly progress to AIDS but those with HLA-B*27 and HLA-B*57 spare disease progression. Previous studies have suggested that viral mutation may prevent a robust immune response against the virus in these with HLA-B*35Px. However, the functionality of HIV-specific CD8(+)T cells restricted by HLA-B*35Px remains unclear. In this study, we demonstrate that HIV-specific CD8(+)T cells restricted by HLA-B*35Px (HLA-B*35:03 and HLA-B*35:02) exhibit an impaired phenotype (e.g. low proliferative capacity, poor cytotoxic molecules expression and, poor cytokine production ability). Interestingly, CD8(+)T cells restricted by HLA-B*27/B*57 evade regulatory T cells (Tregs) suppression but not those restricted by non-HLA-B*27/B*57. CD8(+)T cells restricted by non-HLA-B*27/B*57 when encountering their epitopes upregulate TIM-3 but not those restricted by HLA-B*27/B*57 and HLA-B*35Px. As a result, CD8(+)T cells restricted by non-HLA-B*27/B*57 become suppressed by Tregs via TIM-3: Galectin-9 interactions. Strikingly, CD8(+)T cells restricted by HLA-B*35Px upregulate CTLA-4 when encountering their epitopes, which render them to an exhausted phenotype. This differential response is linked to the up-regulation of Eomes, Blimp-1 but low T-bet expression in CD8(+)T cells restricted by HLA-B*35Px. These results implicate that reinvigoration of these cells might be feasible using an anti-CTLA-4 antibody.