CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.
EMBO Mol Med. 2024 Aug;16(8):1755-1790. doi: 10.1038/s44321-024-00106-1. Epub 2024 Jul 19.
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.
慢性感染，包括由结核分枝杆菌（Mtb）引起的结核病（TB），可诱导宿主免疫衰竭。然而，这一过程中涉及的关键检查点分子和潜在的调节机制在很大程度上仍未得到明确，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，我们通过采用飞行时间质谱流式细胞术和转录谱分析系统地分析自然杀伤（NK）细胞表面受体，鉴定出白细胞免疫球蛋白样受体 B1（LILRB1）作为一个关键的检查点受体，它定义了一个与 TB 相关的细胞亚群（LILRB1 NK 细胞），并在 TB 中驱动 NK 细胞衰竭。从机制上讲，感染了 Mtb 的巨噬细胞显示出高水平的人白细胞抗原-G（HLA-G），其上调并激活 NK 细胞上的 LILRB1，通过酪氨酸磷酸酶 SHP1/2 抑制丝裂原活化蛋白激酶（MAPK）信号传导，从而损害其功能。此外，LILRB1 阻断恢复了免疫人源化小鼠中 NK 细胞依赖的抗 Mtb 免疫。因此，LILRB1-HLA-G 轴构成了 TB 中的 NK 细胞免疫检查点，并可作为有前途的免疫治疗靶点。
