A Specialized CD107a+ Macrophage Subset Drives Selective Mycobacterial Phagocytosis

Macrophages are essential for pathogen clearance, yet phagocytic specialization among subsets is poorly defined. Bone marrow-derived macrophages cultured with L929 supernatant or M-CSF separate into FSCloSSCloF4/80loCD11blo (FSCloSSClo) and FSChiSSChiF4/80hiCD11bhi (FSChiSSChi) subsets. Transcriptomic and functional analyses reveal that FSCloSSClo cells possess a hyperphagocytic program driven by enhanced actin cytoskeleton regulators (e.g., Arp2/3) and pro-inflammatory signaling (NF-{kappa}B). These cells excel at internalizing Mycobacterium tuberculosis virulent H37Rv and BCG through actin-mediated, cytochalasin D-sensitive mechanisms. High surface CD107a (LAMP1) expression marks this hyperphagocytic subset and correlates strongly with mycobacterial uptake. FSCloSSClo macrophages produce more TNF and IL-6 upon mycobacterial or TLR2/TLR5 stimulation yet retain IFN-{gamma}-mediated killing capacity. In vivo, CD107a alveolar macrophages in BCG-infected lungs preferentially capture bacilli and upregulate CD195, recapitulating the in vitro phenotype. These findings establish CD107a as a key surface marker of a hyperphagocytic macrophage subset and highlight its role in selective mycobacterial phagocytosis, providing new mechanistic understanding relevant to tuberculosis host defense and therapeutic development. HighlightsO_LIBone marrow-derived FSCloSSCloF4/80loCD11blo macrophage subset excels at M. tuberculosis and BCG uptake C_LIO_LIHyperphagocytic macrophages mount rapid pro-inflammatory TNF/IL-6 responses C_LIO_LICD107a (LAMP1) identifies a pre-existing hyperphagocytic macrophage subset in vitro and in vivo C_LIO_LIBCG infection triggers CD195 (CCR5) upregulation selectively on CD107a alveolar macrophages C_LI