Crosstalk between Stromal Cells and Macrophages Shapes Host Immunity to Mycobacteria

SUMMARY Granulomas are disease-defining heterocellular tissue structures in mycobacterial infections. They play a multifaceted role ranging from containing the pathogen to causing tissue destruction. Here, we established a mature peritoneal granuloma model in C57BL/6 mice to investigate the dynamic cell-cell interactions during mycobacterial infection, including long-term immune alterations in serous cavities as important sites of disease manifestation. We found that mycobacteria reside in stromal cells, which actively modulate the local tissue environment and shape macrophage responses, particularly through formation of chemokines and colony-stimulating factor 1. Chronic infection induces sustained reprogramming and diversification of stromal cells toward specialized, immune-like states, including active transfer of mycobacteria to macrophages and a pronounced interferon response. Consequently, stromal cells acquire immunoregulatory properties and support pathogen handling, monocyte recruitment and macrophage maturation, thereby playing a decisive role in granuloma formation and thus in the immune response to mycobacteria. HIGHLIGHTS A novel peritoneal mycobacterial infection model reveals heterocellular crosstalk in mature granulomas. Mycobacterial infections persistently reshape immune architecture of serous cavities as important disease sites. Stromal cells act as mycobacterial host cells and acquire immune effector functions. Stromal cells co-organize the tissue host-pathogen interface by recruiting and directly communicating with bone marrow-derived monocytes.