2. Academic Validation
  3. LILRB1-HLA-G axis defines a checkpoint driving natural killer cell exhaustion in tuberculosis

LILRB1-HLA-G axis defines a checkpoint driving natural killer cell exhaustion in tuberculosis

  • EMBO Mol Med. 2024 Aug;16(8):1755-1790. doi: 10.1038/s44321-024-00106-1.
Jing Wang # 1,  Qiyao Chai # 1,  Zehui Lei # 1 2,  Yiru Wang # 1 2,  Jiehua He # 1 2,  Pupu Ge 1 2,  Zhe Lu 1 2,  Lihua Qiang 1 2,  Dongdong Zhao 1 2,  Shanshan Yu 3,  Changgen Qiu 1 2,  Yanzhao Zhong 1 2,  Bing-Xi Li 1,  Lingqiang Zhang 4,  Yu Pang 5,  George Fu Gao 6 7,  Cui Hua Liu 8 9
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • 2 Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.
  • 3 Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China.
  • 4 State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China.
  • 5 Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China. py@bjxkyy.cn.
  • 6 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. gaof@im.ac.cn.
  • 7 Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China. gaof@im.ac.cn.
  • 8 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. liucuihua@im.ac.cn.
  • 9 Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China. liucuihua@im.ac.cn.
  • # Contributed equally.
PMID: 39030302 DOI: 10.1038/s44321-024-00106-1
Abstract

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.

Keywords

Checkpoint Molecule; Immunotherapy; Leukocyte Immunoglobulin Like Receptor B1 (LILRB1); Natural Killer Cell; Mycobacterium tuberculosis (Mtb).

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