The mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. However, considering that these characteristics are often overlapping, the distinction between and classification of these cell types has been challenging. In this Opinion article, we propose a unified nomenclature for the MPS. We suggest that these cells can be classified primarily by their ontogeny and secondarily by their location, function and phenotype. We believe that this system permits a more robust classification during both steady-state and inflammatory conditions, with the benefit of spanning different tissues and across species.

Lymphoid tissue plasmacytoid and conventional dendritic cells (DCs) are continuously regenerated from hematopoietic stem cells. The cytokine dependence and biology of plasmacytoid and conventional DCs suggest that regeneration might proceed through common DC-restricted developmental intermediates. By selecting for cytokine receptor expression relevant to DC development, we identify here highly cycling Lin(-)c-Kit(int)Flt3(+)M-CSFR(+) cells with a distinct gene-expression profile in mouse bone marrow that, on a clonal level in vitro and as a population both in vitro and in vivo, efficiently generated plasmacytoid and conventional DCs but no other lineages, which increased in number after in vivo injection of the cytokine Flt3 ligand. These clonogenic common DC progenitors thus define a cytokine-regulated DC developmental pathway that ensures the supply of various DC populations.

Toll-like receptors (TLRs) are pattern recognition receptors that trigger innate immunity. In this study we investigated the expression of 10 TLRs in human naive and memory B-cell subsets. We report that in human naive B cells most TLRs are expressed at low to undetectable levels, but the expression of TLR9 and TLR10 is rapidly induced following B-cell-receptor ( IntroductionToll-like receptors (TLRs) are pattern recognition receptors that trigger innate immunity, providing both immediate protective responses against pathogens and instructing the adaptive immune response through the induction of dendritic cell recruitment and maturation. 1-4 TLR triggering results in nuclear factor kappa B (NF-B)-mediated activation of inflammatory genes. 5 Ten TLRs have been described in humans, and agonists have been defined for 9 of them. 6 TLRs can function as homodimers or heterodimers, increasing the repertoire of specificities. 7 TLR1, TLR2, and TLR6 are triggered by peptidoglycan and other microbial products, 8,9 TLR3 by double-stranded RNA, 10 TLR4 by lipopolysaccharide (LPS), 11 TLR5 by flagellin, 12 TLR7 and TLR8 by imidazoquinolines, 6,13 and TLR9 by unmethylated CpG DNA. [14][15][16][17][18][19][20][21] TLRs are differentially expressed in dendritic cell (DC) subsets. [22][23][24] Monocytes and myeloid DCs express TLR2 and TLR4 and respond to peptidoglycan and LPS, while plasmacytoid DCs express a reciprocal pattern-namely, TLR7 and TLR9 and respond to CpG. The induction of DC maturation by TLRs represents the functional link between innate and adaptive response. 1,25 TLR expression can be regulated; for instance, interferon-␥ (IFN-␥) up-regulates TLR4 expression in human phagocytes, enhancing their capacity to respond to LPS. 26 Mouse B cells proliferate and differentiate in response to LPS or CpG, 14,27 indicating that they express functional TLR4 and TLR9. Human B cells also respond to CpG, 19 but recent data indicate that memory B cells are more responsive than naive B cells, raising the possibility that TLR expression may be differentially regulated in human naive and memory B cells. 28 We report here that in human naive B cells TLRs are expressed at low to undetectable levels but their expression is rapidly up-regulated by B-cell-receptor (BCR) triggering. In contrast, memory B cells express several TLRs at constitutively high levels. The differential expression correlates with responsiveness to CpG DNA, an agonist of TLR9, and points to a relevant difference between human and mouse B cells. Thus, in humans TLRs are downstream of BCR and play a role in the late phase of acquired immunity. Materials and methods Cell isolation and cultureB lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) using CD19 microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany) and further purified by cell sorting using a FACSVantage (Becton Dickinson, San Jose, CA). Cells were stained with directly labeled antibodies to CD27 (Pharmingen, San Diego, CA) (to identify memory B cells) and appropriate combinations...

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Type I interferons (IFNs), a family of cytokines, orchestrate numerous biological and cellular processes1, 2, 3. Although it is well known that type I IFNs are essential for establishing the host antiviral state4, their role in hematopoietic homeostasis has not been studied. Here we show that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs) and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type I IFN signaling5, 6, preserves the self-renewal and multilineage differentiation capacity of HSCs. HSCs were substantially less abundant in the bone marrow of Irf2-/- as compared to Irf2+/- mice. Irf2-/- HSCs showed enhanced cell cycling status and failed to produce hematopoietic cells in competitive repopulation assays, and the reconstituting capacity of Irf2-/- HSCs was restored by disabling type I IFN signaling in these cells. In wild-type mice, injection of poly(I:C), an inducer of type I IFN signaling, or IFN- induced HSC proliferation, and chronic type I IFN signaling further reduced the number of quiescent HSCs. Notably, combined poly(I:C) and 5-fluorouracil (5-FU) treatment allowed exogenous HSC engraftment and hematopoietic reconstitution in WT mice. Our findings provide insight into the molecular basis for the maintenance of HSC quiescence and may lead to improvements in bone marrow transplantation and type I IFN-based therapies for viral infection and cancer.