ABSTRACT
Monocytes give rise to macrophages and dendritic cells (DCs) under steady-state and inflammatory conditions, thereby contributing to host defense and tissue pathology. A common monocyte progenitor (cMoP) that is strictly committed to the monocyte lineage has been recently identified in mice. Here, we identified human cMoPs as a CLEC12AhiCD64hi subpopulation of conventional granulocyte-monocyte progenitors (cGMPs) in umbilical cord blood and in bone marrow. Human cMoPs gave rise to monocyte subsets without showing any potential for differentiating into myeloid or lymphoid cells. Within the cGMP population, we also identified revised GMPs that completely lacked DC and lymphoid potential. Collectively, our findings expand and revise the current understanding of human myeloid cell differentiation pathways.
Subject(s)
Cell Differentiation , Clonal Evolution , Monocyte-Macrophage Precursor Cells/cytology , Monocyte-Macrophage Precursor Cells/metabolism , Monocytes/cytology , Monocytes/metabolism , Animals , Antigens, CD/metabolism , Biomarkers , Cell Cycle , Cell Lineage , Cell Proliferation , Cells, Cultured , Cluster Analysis , Cytokines/metabolism , Fetal Blood/cytology , Gene Expression Profiling , Humans , Immunophenotyping , MiceABSTRACT
Because immune responses simultaneously defend and injure the host, the immune system must be finely regulated to ensure the host's survival. Here, we have shown that when injected with high Toll-like receptor ligand doses or infected with lymphocytic choriomeningitis virus (LCMV) clone 13, which has a high viral turnover, inflammatory monocyte-derived dendritic cells (Mo-DCs) engulfed apoptotic erythroid cells. In this process, called hemophagocytosis, phosphatidylserine (PS) served as an "eat-me" signal. Type I interferons were necessary for both PS exposure on erythroid cells and the expression of PS receptors in the Mo-DCs. Importantly, hemophagocytosis was required for interleukin-10 (IL-10) production from Mo-DCs. Blocking hemophagocytosis or Mo-DC-derived IL-10 significantly increased cytotoxic T cell lymphocyte activity, tissue damage, and mortality in virus-infected hosts, suggesting that hemophagocytosis moderates immune responses to ensure the host's survival in vivo. This sheds light on the physiological relevance of hemophagocytosis in severe inflammatory and infectious diseases.
Subject(s)
Apoptosis/immunology , Dendritic Cells/immunology , Lymphocytic choriomeningitis virus/immunology , Phagocytosis , Animals , Cell Differentiation , Dendritic Cells/metabolism , Erythroid Cells/immunology , Interferon Type I/metabolism , Interleukin-10/biosynthesis , Lymphocyte Activation , Lymphocytic Choriomeningitis/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/immunology , Monocytes/metabolism , Phosphatidylserines/metabolism , Receptors, Cell Surface/metabolism , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
Macrophage and dendritic cell (DC) progenitors (MDPs) and common DC progenitors (CDPs) are bone marrow (BM) progenitors with DC differentiation potential. However, both MDPs and CDPs give rise to large numbers of conventional DCs (cDCs) and few plasmacytoid DCs (pDCs), implying that more dedicated pDC progenitors remain to be identified. Here we have described DC progenitors with a prominent pDC differentiation potential. Although both MDPs and CDPs express the macrophage colony stimulating factor (M-CSF) receptor (M-CSFR), the progenitors were confined to a M-CSFR(-) fraction, identified as Lin(-)c-Kit(int/lo)Flt3(+)M-CSFR(-), and expressed high amounts of E2-2 (also known as Tcf4) an essential transcription factor for pDC development. Importantly, they appeared to be directly derived from either CDPs or lymphoid-primed multipotent progenitors (LMPPs). Collectively, our findings provide insight into DC differentiation pathways and may lead to progenitor-based therapeutic applications for infection and autoimmune disease.