T and B lymphocyte differentiation from hematopoietic stem cell

Until the past few years, it has been thought that lymphoid and myeloid lineage segregation represents the first step of lineage restriction during hematopoiesis from hematopoietic stem cell. Recent investigation of the cell populations within multipotent progenitors in the bone marrow has led to new understanding of how hematopoietic stem cells diversify into different hematopoietic cell types. This review focuses on the recent advances in understanding the developmental events that occur during hematopoietic stem cell specification into the T and B lymphocyte lineages in adult mice.     

Developmental plasticity of lymphoid progenitors

The identification of the common lymphoid progenitors in mouse bone marrow allows us to directly assess the regulatory mechanisms of lymphoid lineage commitment. The unexpected finding of a latent myeloid differentiation potential in lymphoid progenitors sheds light on the importance of cytokine receptor expression at this stage. We will discuss the biological nature of common lymphoid progenitors as a model of differentiation from multipotent to lineage committed progenitors. Elucidation of this hidden differentiation potential in progenitors will help further our understanding of the molecular mechanisms that control the cell fate determination of not only common lymphoid progenitors, but also their ancestors, hematopoietic stem cells, and their descendents such as committed T and B cell progenitors.     

A close developmental relationship between the lymphoid and myeloid lineages

The classic dichotomy model of hematopoiesis postulates that the first step of differentiation beyond the multipotent hematopoietic stem cell generates the common myelo-erythroid progenitors and common lymphoid progenitors (CLPs). Previous studies in fetal mice showed, however, that myeloid potential persists in the T- and B-cell branches even after these lineages have diverged, indicating that the simple dichotomy model is invalid, at least for fetal hematopoiesis. Nevertheless, CLPs have persisted in models of adult hematopoiesis; results from several groups support the presence of CLPs in bone marrow. Recent evidence challenges the dichotomy model in the adult, and it is proposed here that the alternative myeloid-based model is applicable to both fetal and adult hematopoiesis.     

Foxp3+ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow

Foxp3⁺ Treg cells are crucial for maintaining T‐cell homeostasis, but their role in B‐cell homeostasis remains unclear. Here, we found that Foxp3 mutant scurfy mice had fewer B‐lineage cells and progenitors, including common lymphoid progenitors and lymphoid‐primed multipotent progenitors, but higher myeloid‐lineage cell numbers in BM compared with WT littermates. Homeostasis within the HSC compartment was also compromised with apparent expansion of long‐ and short‐term HSCs. This abnormality was due to the lack of Treg cells, but not to the Treg‐cell extrinsic functions of Foxp3 or cell‐autonomous defects. Among cytokines enriched in the BM of scurfy mice, IFN‐γ affected only B lymphopoiesis, but GM‐CSF, TNF, and IL‐6 collectively promoted granulopoiesis at the expense of B lymphopoiesis. Neutralization of these three cytokines reversed the hematopoietic defects on early B‐cell progenitors in scurfy mice. Treg cells ensured B lymphopoiesis by reducing the production of these cytokines by effector T cells, but not by directly affecting B lymphopoiesis. These results suggest that Treg cells occupy an important niche in the BM to protect B‐lineage progenitor cells from excessive exposure to a lymphopoiesis‐regulating milieu.     

Positive and negative regulation of the myeloid dendritic cell lineage.

Recent advances have revealed that dendritic cells (DCs) are not a single cell type, but a system of cells that are phenotypically and functionally diverse. DC subtypes stemming from the myeloid and lymphoid lineages promote a diversity of immune responses ranging from the stimulation of naive T and B cell responses to the down-regulation of T cell responses. Although differences in antigen handling are linked to DC developmental stages in the myeloid DC lineage, the particular type of immune response elicited may be determined by a specific DC subtype. This review summarizes key regulatory mechanisms controlling the development of myeloid lineage DCs from multipotent progenitors. Emphasis is placed on describing a highly orchestrated series of proliferative, apoptotic, and developmental events involving granulocyte-macrophage colony-stimulating factor, transforming growth factor beta, and the tumor necrosis factor alpha, CD95, and bcl-2 protein families.     

The human embryo, but not its yolk sac, generates lympho-myeloid stem cells: mapping multipotent hematopoietic cell fate in intraembryonic mesoderm

We have traced emerging hematopoietic cells along human early ontogeny by culturing embryonic tissue rudiments in the presence of stromal cells that promote myeloid and B cell differentiation, and by assaying T cell potential in the NOD-SCID mouse thymus. Hematogenous potential was present inside the embryo as early as day 19 of development in the absence of detectable CD34+ hematopoietic cells, and spanned both lymphoid and myeloid lineages from day 24 in the splanchnopleural mesoderm and derived aorta where CD34+ progenitors appear at day 27. By contrast, hematopoietic cells arising in the third week yolk sac, as well as their progeny at later stages, were restricted to myelopoiesis and therefore are unlikely to contribute to definitive hematopoiesis in man.     

Effects of vitamin D on the growth of normal and malignant B-cell progenitors.

As the effects of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25-(OH)2-D3) (VD, calcitriol) on the proliferation and differentiation potential of normal and leukaemic cells in vitro of myeloid lineage are known, we investigated the response to VD on the growth of both normal and malignant lymphoid progenitors. Effects of vitamin D on normal human lymphoid progenitors and B lineage acute lymphoblastic leukaemia (ALL) progenitors were assessed by using an in vitro cell colony assay specific for either B or T cell lineages. The expression of VDR on B untreated malignant progenitors at diagnosis was investigated by RT-PCR analysis. VD induced a significant inhibition of normal lymphoid cell progenitors growth of both T and B lineage. VD inhibited significantly also the growth of malignant B cell lineage lymphoid progenitors, without inducing cytotoxic effect. As it has been reported that VD effects on activated lymphocytes are mediated by 1,25-(OH)2-D3 nuclear receptor (VDR), we investigated VDR expression on malignant B cell progenitors. We did not detect VDR expression on these cells examined at diagnosis. We demonstrated that VD inhibited in vitro the clonogenic growth of both normal and malignant lymphoid B cell progenitors and that this inhibitory effect on malignant B cell progenitors was not related to VDR. Our work contributes to understanding of the mechanism of action of this hormone in promoting cellular inhibition of clonal growth of malignant lymphoid B cell progenitors, suggesting that the regulation of some critical growth and differentiation factor receptors could be a key physiological role of this hormone.     

Cell circuits and niches controlling B cell development

Studies over the last decade uncovered overlapping niches for hematopoietic stem cells (HSCs), multipotent progenitor cells, common lymphoid progenitors, and early B cell progenitors. HSC and lymphoid niches are predominantly composed by mesenchymal progenitor cells (MPCs) and by a small subset of endothelial cells. Niche cells create specialized microenvironments through the concomitant production of short‐range acting cell‐fate determining cytokines such as interleukin (IL)‐7 and stem cell factor and the potent chemoattractant C‐X‐C motif chemokine ligand 12. This type of cellular organization allows for the cross‐talk between hematopoietic stem and progenitor cells with niche cells, such that niche cell activity can be regulated by the quality and quantity of hematopoietic progenitors being produced. For example, preleukemic B cell progenitors and preB acute lymphoblastic leukemias interact directly with MPCs, and downregulate IL‐7 expression and the production of non‐leukemic lymphoid cells. In this review, we discuss a novel model of B cell development that is centered on cellular circuits formed between B cell progenitors and lymphopoietic niches.     

Divergent models of lymphoid lineage specification: do clonal assays provide all the answers?

Summary: Hematopoietic stem cells that drive blood development in mouse and man have been well characterized in recent years. In contrast, detailed analysis of the next stages of development, the progenitor cells that have begun to differentiate along specific hematopoietic lineages, is now only in its infancy. The process of myeloid differentiation has been relatively accessible to experimental manipulation due to the availability of culture systems able to support the progenitors for myeloid lineages, and the identification of cytokines capable of driving myeloid differentiation. Studies of early lymphoid differentiation, however, have lagged behind. In particular, the characterization of the first progenitors for the lymphoid lineages is far from complete, due mainly to inefficient assay systems for growing these cell lineages in vitro . Two laboratories have published conflicting data regarding the specification of lymphoid lineages in the mouse. Both groups of investigators utilize elegant clonal approaches to characterize progenitor cell subsets. While these experiments define lineage potential in the most rigorous manner possible, the divergent results suggest that clonal assays must be supplemented with more physiologic studies in order to define the actual differentiation pathways that function in vivo .     

Bipotential B-macrophage progenitors are present in adult bone marrow

According to the current model of adult hematopoiesis, differentiation of pluripotential hematopoietic stem cells into common myeloid- and lymphoid-committed progenitors establishes an early separation between the myeloid and lymphoid lineages. This report describes a rare and previously unidentified CD45R-CD19+ B cell progenitor population in postnatal bone marrow that can also generate macrophages. In addition to the definition of this B-lineage intermediate, the data indicate that a developmental relationship between the B and macrophage lineages is retained during postnatal hematopoiesis.