Boosting immune cell function by targeting the coinhibitory 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 anti–PD-1 monoclonal antibody developed worse disease and higher granuloma bacterial loads compared with 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 anti–PD-1–treated macaques were not increased in number or function in granulomas, expressed increased levels of CTLA-4, and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of anti–PD-1–treated animals, multiple proinflammatory 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. Last, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota before infection in individual macaques. Therefore, PD-1–mediated coinhibition is required for control of Mtb infection in macaques, perhaps because of its role in dampening detrimental inflammation and allowing for normal CD4 T cell responses.

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方面有应用。在这里，我们检查了 PD-1 在结核分枝杆菌中的作用(Mtb) 感染恒河猴。与同种型对照治疗的猴子相比，用抗 PD-1 单克隆抗体治疗的动物出现了更严重的疾病和更高的肉芽肿细菌负荷。PD-1 阻断增加了肉芽肿 Mtb 特异性 CD8 T 细胞的数量和功能。相比之下，抗 PD-1 治疗的猕猴中 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 水平升高，并且在实时成像研究中表现出病灶内运输减少。在抗 PD-1 治疗动物的肉芽肿中，多种促炎细胞因子升高，更多细胞因子与细菌负荷相关，从而确定了半胱天冬酶 1 在 PD-1 阻断后结核病恶化中的作用。最后的，发现 PD-1 阻断后 Mtb 细菌负荷增加与单个猕猴感染前肠道微生物群的组成有关。因此，PD-1 介导的共抑制是控制猕猴 Mtb 感染所必需的，这可能是因为它在抑制有害炎症和允许正常的 CD4 T 细胞反应方面的作用。