Abstract: The immune response to mycobacteria is characterized by granuloma formation, which features multinucleated giant cells as a unique macrophage type. We previously found that multinucleated giant cells result from Toll-like receptor-induced DNA damage and cell autonomous cell cycle modifications. However, the giant cell progenitor identity remained unclear. Here, we show that the giant cell-forming potential is a particular trait of monocyte progenitors. Common monocyte progenitors potently produce cytokines in response to mycobacteria and their immune-active molecules. In addition, common monocyte progenitors accumulate cholesterol and lipids, which are prerequisites for giant cell transformation. Inducible monocyte progenitors are so far undescribed circulating common monocyte progenitor descendants with high giant cell-forming potential. Monocyte progenitors are induced in mycobacterial infections and localize to granulomas. Accordingly, they exhibit important immunological functions in mycobacterial infections. Moreover, their signature trait of high cholesterol metabolism may be piggy-backed by mycobacteria to create a permissive niche

Abstract: The interface between the mammalian host and its environment is formed by barrier tissues, for example, of the skin, and the respiratory and the intestinal tracts. On the one hand, barrier tissues are colonized by site-adapted microbial communities, and on the other hand, they contain specific myeloid cell networks comprising macrophages, dendritic cells, and granulocytes. These immune cells are tightly regulated in function and cell number, indicating important roles in maintaining tissue homeostasis and immune balance in the presence of commensal microorganisms. The regulation of myeloid cell density and activation involves cell-autonomous 'single-loop circuits' including autocrine mechanisms. However, an array of microenvironmental factors originating from nonimmune cells and the microbiota, as well as the microanatomical structure, impose additional layers of regulation onto resident myeloid cells. This review discusses models integrating these factors into cell-specific programs to instruct differentiation and proliferation best suited for the maintenance and renewal of immune homeostasis in the tissue-specific environment