Crosstalk between Stromal cells and Macrophages Shapes Host Immunity to Mycobacteria

Granulomas are disease-defining heterocellular tissue structures in mycobacterial infections and play ambiguous roles ranging from pathogen containment to tissue destruction. Here, we established a mature peritoneal granuloma model in C57BL/6 mice to investigate dynamic cell-cell-interactions during mycobacterial infection, including long-term immune alterations within serous cavities as important disease manifestation sites. We show that mycobacteria reside in stromal cells, which modulate the local tissue milieu and shape macrophage responses, particularly through chemokine and colony-stimulating factor 1 production. 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 critically shaping granuloma formation and contributing to containment of mycobacteria. HIGHLIGHTSO_LIA novel peritoneal mycobacterial infection model reveals heterocellular crosstalk in mature granulomas. C_LIO_LIMycobacterial infections persistently reshape immune architecture of serous cavities as important disease sites. C_LIO_LIStromal cells act as mycobacterial host cells and acquire immune effector functions. C_LIO_LIStromal cells co-organize the tissue host-pathogen interface by recruiting and directly communicating with bone marrow-derived monocytes. C_LI