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Figure 1: Mononuclear phagocyte differentiation in mouse and human. Hematopoiesis in mouse and human begins from the hematopoietic stem cells (HSCs). The HSCs are self-renewing with clonogenic and multipotent features, giving rise to all blood and tissue-resident immune cells. A very small number of HSCs generate immune cells de novo through a multistep differentiation process passing through multilineage progenitors first and to committed progenitors later. All of this process is strictly regulated according to physiological requirements, be it in the steady state or in response to external perturbations, such as infection. Aging also profoundly affects the function of the immune system. The phenomenon is attributable mainly to changes in the HSC compartment that probably gradually reduces its capacity for self-renewal, leading to a progressive reduction in the numbers of immune cells. Myeloid differentiation starts from a common myeloid progenitor (CMP) in the bone marrow. In the mouse, the destiny of CMP is better characterized compared to that of the human counterpart. The CMP generates macrophage-(Mf-) dendritic cell (DC) precursors (MDPs), which are considered the direct progenitor of Gr1+ and Gr1 monocytes in the blood. Besides monocytes, the MDP differentiates into the common DC precursor (CDP), which in turn generates plasmacytoid DC (pDC) and progenitors for conventional DC (pre-cDC). pDC and myeloid DC diverge at the CDP stage. Pre-cDCs migrate out of the BM through the blood circulation into secondary lymphoid tissues (spleen and lymph nodes), where they replenish both CD8+ and CD8 DC in the tissues. In humans, CMPs differentiate to granulocyte-macrophage (CFU-GM) precursor, which give rise to monocytes (CD14hiCD16 and CD14loCD16+) through subsequent differentiation steps, monoblast first, followed by promonocyte. A DC precursor (CFU-DC) derived from CD34+ HSC with unique differentiation potential towards DC has been identified in bone marrow of the mouse, suggesting that a DC progenitor might exist in humans. Blood monocytes (Gr1+ and Gr1 in mouse, CD14hiCD16 and CD14loCD16+ in humans) migrate to nonlymphoid tissues and generate macrophages (Mfs) and interstitial DC (iDC). In the presence of environmental perturbation in vivo or of cytokines in vitro, Gr1+ or Gr1 monocytes in mice and CD16+ or CD16 monocytes in humans differentiate into Langerhans cells (LCs) in the epidermis, as well as inflammatory DC (Inf.DC). LCs are generated by a dermal long-term precursor (pLC) in the steady state. Finally, migratory DC (Mig.DC) moves between nonlymphoid and lymphoid compartments.