Antibody-Mediated LILRB2-Receptor Antagonism Induces Human Myeloid-Derived Suppressor Cells to Kill Mycobacterium tuberculosis

Frontiers in Immunology

Yitian Xu¹  Licheng Zhang¹  Ping-Ying Pan¹  Sunny Mai¹  Shu-Hsia Chen¹  Arshad Khan²  Chinnaswamy Jagannath²  Vipul K. Singh²  Abhishek Mishra²  Blanca I. Restrepo⁴ 

[1] Center for Immunotherapy Research and Cancer Center, Weill Cornell Medicine, Houston Methodist Research Institute,Houston, TX, United States;Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, TX, United States;School of Public Health at Brownsville, University of Texas Health Science Center Houston, Brownsville, TX, United States;South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, Edinburg, TX, United States;

关键词: tuberculosis;    MDSC (myeloid-derived suppressor cell);    LILRB;    monoclonal antibody;    Mycobacterium;   

DOI  :  10.3389/fimmu.2022.865503

来源: DOAJ

【 摘 要 】

Tuberculosis is a leading cause of death in mankind due to infectious agents, and Mycobacterium tuberculosis (Mtb) infects and survives in macrophages (MФs). Although MФs are a major niche, myeloid-derived suppressor cells (MDSCs) are an alternative site for pathogen persistence. Both MФs and MDSCs express varying levels of leukocyte immunoglobulin-like receptor B (LILRB), which regulate the myeloid cell suppressive function. Herein, we demonstrate that antagonism of LILRB2 by a monoclonal antibody (mab) induced a switch of human MDSCs towards an M1-macrophage phenotype, increasing the killing of intracellular Mtb. Mab-mediated antagonism of LILRB2 alone and its combination with a pharmacological blockade of SHP1/2 phosphatase increased proinflammatory cytokine responses and phosphorylation of ERK1/2, p38 MAPK, and NF-kB in Mtb-infected MDSCs. LILRB2 antagonism also upregulated anti-mycobacterial iNOS gene expression and an increase in both nitric oxide and reactive oxygen species synthesis. Because genes associated with the anti-mycobacterial function of M1-MФs were enhanced in MDSCs following mab treatment, we propose that LILRB2 antagonism reprograms MDSCs from an immunosuppressive state towards a pro-inflammatory phenotype that kills Mtb. LILRB2 is therefore a novel therapeutic target for eradicating Mtb in MDSCs.

【 授权许可】

Unknown