Boosting immune cell function by targeting the co-inhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here we examine the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with αPD-1 mAb developed worse disease and higher granuloma bacterial loads compared to isotype control treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in αPD-1 treated macaques were not increased in number or function in granulomas, upregulated high levels of CTLA-4 and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of αPD-1 treated animals, multiple pro-inflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Lastly, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota prior to infection in individual macaques. Therefore, PD-1-mediated co-inhibition is required for control of Mtb infection in macaques, perhaps due to its role in dampening detrimental inflammation as well as allowing for normal CD4 T cell responses.

中文翻译：

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PD-1阻滞加重了猕猴的结核分枝杆菌感染

通过靶向共抑制受体PD-1来增强免疫细胞功能可能在治疗慢性感染中具有应用。在这里，我们检查了猕猴的结核分枝杆菌（Mtb）感染期间PD-1的作用。与同型对照治疗的猴子相比，用αPD-1mAb治疗的动物病情恶化，肉芽肿细菌负荷更高。PD-1阻断增加了肉芽肿Mtb特异性CD8 T细胞的数量和功能。相反，αPD-1处理的猕猴中的Mtb特异性CD4 T细胞在肉芽肿中的数量或功能没有增加，CTLA-4的高水平上调并在实时成像研究中显示出病灶内运输减少。在接受αPD-1治疗的动物肉芽肿中，多种促炎性细胞因子升高，并且更多的细胞因子与细菌负荷相关，导致确定caspase 1在PD-1阻断后结核病恶化中的作用。最后，发现PD-1阻断后增加的Mtb细菌载量与个别猕猴感染前肠道菌群的组成有关。因此，PD-1介导的共抑制作用是控制猕猴Mtb感染所必需的，这可能是由于其在减轻有害炎症以及正常CD4 T细胞应答中的作用。