Chronic infections, including Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), can induce host immune exhaustion. However, the key checkpoint molecules involved in this process and the underlying regulatory mechanisms remain largely undefined, which impede the application of checkpoint-based immunotherapy in infectious diseases. Here, through adopting time-of-flight mass cytometry and transcriptional profiling to systematically analyze natural killer (NK) cell surface receptors, we identify leukocyte immunoglobulin like receptor B1 (LILRB1) as a critical checkpoint receptor that defines a TB-associated cell subset (LILRB1+ NK cells) and drives NK cell exhaustion in TB. Mechanistically, Mtb-infected macrophages display high expression of human leukocyte antigen-G (HLA-G), which upregulates and activates LILRB1 on NK cells to impair their functions by inhibiting mitogen-activated protein kinase (MAPK) signaling via tyrosine phosphatases SHP1/2. Furthermore, LILRB1 blockade restores NK cell-dependent anti-Mtb immunity in immuno-humanized mice. Thus, LILRB1-HLA-G axis constitutes a NK cell immune checkpoint in TB and serves as a promising immunotherapy target.

中文翻译：

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LILRB1-HLA-G 轴定义了结核病中驱动自然杀伤细胞耗竭的检查点。


慢性感染，包括结核分枝杆菌 (Mtb) 引起的结核病 (TB)，可导致宿主免疫衰竭。然而，参与这一过程的关键检查点分子及其潜在的调节机制在很大程度上仍不清楚，这阻碍了基于检查点的免疫疗法在传染病中的应用。在这里，通过采用飞行时间质谱流式细胞术和转录分析系统分析自然杀伤（NK）细胞表面受体，我们将白细胞免疫球蛋白样受体B1（LILRB1）确定为定义结核病相关细胞亚群的关键检查点受体。 LILRB1+ NK 细胞）并导致 TB 中 NK 细胞耗竭。从机制上讲，感染 Mtb 的巨噬细胞表现出人类白细胞抗原 G (HLA-G) 的高表达，该抗原上调并激活 NK 细胞上的 LILRB1，通过酪氨酸磷酸酶 SHP1/2 抑制丝裂原激活蛋白激酶 (MAPK) 信号传导，从而损害其功能。此外，LILRB1 阻断可恢复免疫人源化小鼠中 NK 细胞依赖性抗 Mtb 免疫力。因此，LILRB1-HLA-G 轴构成了 TB 中的 NK 细胞免疫检查点，并可作为有前景的免疫治疗靶点。