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  • Review Article
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Evolving views on the genealogy of B cells

Key Points

  • Several experimental strategies now make it possible to identify and substantially enrich specified cells that have just begun to express lymphoid-related genes while downregulating their potential for non-lymphoid differentiation. These early lymphoid progenitors (ELPs) efficiently produce T cells, B cells, natural killer (NK) cells and some dendritic cells.

  • The generation of ELPs from stem cells is a gradual process, and one that may initially be reversible. Some transcription factors and cytokine receptors that are required for their formation have been identified, but it is remarkable that lymphopoiesis is not totally dependent on any one of them.

  • Reporter mice and panels of monoclonal antibodies are essential for tracking the progeny of stem cells through indiscrete stages of differentiation. However, many of these tools are only applicable in particular circumstances and/or with particular strains of mice.

  • Views about differentiation pathways and milestones are rapidly evolving. No longer viewed as a series of binary fate decisions, there may be divergence and later convergence between haematopoietic cell lineages.

  • Stem cells and ELPs are not confined to osteoblastic niches, and some of the molecules responsible for their positioning, survival, proliferation and differentiation have been identified.

  • Distinctions between antigen-independent, pre-receptor events in the bone marrow and those in the periphery are now blurred by the knowledge that stem and progenitor cells express functional Toll-like receptors (TLRs). Endogenous substances released from damaged or inflamed tissues, as well as pathogen products, can act as differentiation cues, shifting B-cell lymphopoiesis towards the emergency generation of dendritic cells.

  • When used together with the approaches summarized here, fate mapping and disease models will open exciting new lines of investigation. For example, we will learn whether immune effectors produced via different pathways and circumstances have distinctive properties.

Abstract

Many fundamental concepts about immune system development have changed substantially in the past few years, and rapid advances with animal models are presenting prospects for further discovery. However, continued progress requires a clearer understanding of the relationships between haematopoietic stem cells and the progenitors that replenish each type of lymphocyte pool. Blood-cell formation has traditionally been described in terms of discrete developmental branch points, and a single route is given for each major cell type. As we discuss in this Review, recent findings suggest that the process of B-cell formation is much more dynamic.

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Figure 1: Founders of the immune system emerge gradually from an extremely rare subset in the bone marrow.
Figure 2: Progression through the earliest stages of lymphopoiesis is gradual, but bone-marrow cells can be categorized on the basis of expression of various markers.
Figure 3: Early stages of B-cell lymphopoiesis can be influenced by microbial and viral products.

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Acknowledgements

Our work is supported by grants from the National Institutes of Health, USA (AI20069 and AI058162). We are grateful for the helpful comments from our colleagues and especially K. Garrett. We apologize for not being able to cite many relevant primary papers and reviews because of space limitations.

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Correspondence to Paul W. Kincade.

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Glossary

Microarray analysis

A technique for measuring gene transcription. It involves hybridization of fluorescently labelled cDNA prepared from a cell or tissue of interest with glass slides or other surfaces dotted with thousands of oligonucleotides or cDNA, ideally representing all expressed genes in the species.

Multiplex PCR analysis

A variation on conventional PCR assays, in which more than one pair of primers is used to simultaneously amplify target DNA sequences.

Terminal deoxynucleotidyltransferase

(TdT). An enzyme expressed during lymphocyte development that inserts nucleotides into the variable regions of T-cell receptor and immunoglobulin genes, to create junctional diversity.

Gene-reporter mice

Genetically engineered knock-in mice that allow tracking of the expression of a gene of interest. This is achieved by replacing the gene of interest (or part of it) by a sequence that encodes a reporter molecule, such as green fluorescent protein (GFP). When the promoter region of the gene of interest is activated, GFP is expressed and living cells can be visualized by flow cytometry.

Sterile IgH RNA

(Sterile immunoglobulin heavy-chain RNA). A transcript of an unrearranged IgH locus, which does not produce a functional protein. Its presence is thought to reflect the accessibility of the locus for recombination.

B-2 cells

IgMlowIgDhiMAC1B220hiCD23+ cells that originate from bone marrow and are distributed to mucosal and systemic immune compartments for the continuous secretion of antibodies with high affinity and fine specificity.

B-1 cells

IgMhiIgDlowMAC1+B220lowCD23 cells that are dominant in the peritoneal and pleural cavities. Their precursors develop in the fetal liver and omentum, and in adult mice, the size of the B-1-cell population is kept constant owing to the self-renewing capacity of these cells. B-1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that tend to have low affinity and broad specificity.

Osteoclasts

Multinucleated macrophage-related cells that absorb bone.

Angiopoietins

A family of proteins that promote the formation of new blood vessels.

OP9-DLL1 system

Stromal cells derived from osteopetrotic OP/OP mice (OP9 cells) are useful in co-cultures initiated with myeloid progenitor cells because they do not produce macrophage colony-stimulating factor 1 that can cause excessive generation of macrophages and prevent the development of lymphoid cells. When stably transduced to overexpress the Notch ligand delta-like-ligand 1 (DLL1), these cells can support a surprising degree of progression in the T-cell lineage. Adherent layers of OP9-DLL1 stromal cells function like an artificial thymus in culture when lymphoid progenitors are added.

Plasmacytoid dendritic cells

(pDCs). A subset of DCs the microscopic appearance of which resembles plasmablasts. In humans, these DCs can be derived from lineage-negative stem cells in peripheral blood and are the main producers of type I interferons (IFNs) in response to virus infections. Recent studies have identified subsets of type-I-IFN-producing DCs in mice, which are identified by expression of B220, Ly6C and other markers.

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Welner, R., Pelayo, R. & Kincade, P. Evolving views on the genealogy of B cells. Nat Rev Immunol 8, 95–106 (2008). https://doi.org/10.1038/nri2234

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