Mycobacterial infection uncovers plasticity of Kupffer cells

Bona fide Kupffer cells (KCs) are prenatally seeded and show unique functional and immunophenotypic features among tissue macrophages. They are considered as terminally differentiated, and adaptability in disease is attributed to recruited, monocyte-derived KCs. Here, we investigated the extent of KC plasticity and the impact of origin in mycobacterial infections that target macrophages and can persist for months. Fate-mapping combined with high-resolution imaging revealed the emergence of a unique, infection specific KC subset which downregulated the signature markers CLEC4F and VSIG4 (“KC ^low ”). KC ^low were derived from bona fide KCs and located exclusively to granuloma cores. In contrast, monocyte-derived macrophages were contained at the granuloma borders and contributed to this tissue reaction. ATAC and single-cell RNA sequencing identified a specific signature of KC ^low with high antimycobacterial activity and specialization to a hypoxic microenvironment. Despite their fundamental deviation from the classical KC phenotype, KC ^low showed remarkable adaptability, and were capable to return to a homeostatic-like KC state. Accordingly, mycobacterial infections unmask KCs as highly plastic cells, capable of responding to extreme environmental changes.