AUTHOR=Singh Vipul K. , Khan Arshad , Xu Yitian , Mai Sunny , Zhang Licheng , Mishra Abhishek , Restrepo Blanca I. , Pan Ping-Ying , Chen Shu-Hsia , Jagannath Chinnaswamy 

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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.865503

DOI=10.3389/fimmu.2022.865503

ISSN=1664-3224

ABSTRACT=<p>Tuberculosis is a leading cause of death in mankind due to infectious agents, and <italic>Mycobacterium tuberculosis</italic> (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 <italic>iNOS</italic> 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.</p>