Review
Lineage commitment in lymphopoiesis

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Abstract

The mechanisms controlling the commitment of hematopoietic progenitor cells to the lymphoid lineages are still mostly unknown. Recent findings indicate that the earliest phase of B cell development may proceed in two steps. At the onset of B-lymphopoiesis, the transcription factors E2A and EBF coordinately activate the B-cell-specific gene expression program. Subsequently, Pax5 appears to repress the promiscuous transcription of lineage-inappropriate genes and thus commits progenitor cells to the B-lymphoid pathway by suppressing alternative cell fates. B-lineage commitment by Pax5 seems to occur in a stochastic manner in the bone marrow, as indicated by the random activation of only one of the two Pax5 alleles in early pro-B cells. In contrast, loss- and gain-of-function analyses have implicated the Notch1 receptor in the specification of the T cell fate, which may thus be controlled by instructive signals in the thymus.

Introduction

The pluripotent hematopoietic stem cell (HSC) gives rise to all mature cell types of the blood by differentiating through intermediate progenitor cells that undergo lineage commitment and subsequent development along a single pathway. Recent evidence suggests that the lymphoid lineages, consisting of B, T and natural killer (NK) cells, are generated from the hematopoietic stem cell through a common lymphoid progenitor [1]. Despite extensive analyses of hematopoietic cytokines and transcription factors, little is known about the molecular mechanisms underlying lineage commitment. This process is thought to irreversibly restrict the developmental fate of a progenitor cell to a single lineage by establishing a unique gene expression pattern. Expression analyses at the single-cell level have demonstrated that multipotent progenitor cells promiscuously activate regulatory genes of different lineage-affiliated programs, although often at a low level [2].

On the basis of these findings, Enver and Greaves [3] proposed that unilineage commitment involves the repression of lineage-inappropriate genes and the further activation of lineage-specific genes, which results in the suppression of alternative cell fates by consolidating the gene expression program of a single lineage. This model predicts that transcription factors involved in lineage commitment fulfil a dual role as activators and repressors of gene transcription. During the past year, the B-lymphoid-specific transcription factor Pax5 (also termed BSAP [B-cell-specific activator protein]) has been identified by these criteria to be an important regulator of B cell lineage commitment. As yet, a transcription factor playing a similarly important role in T-lymphoid commitment has not been identified. However, signaling through the transmembrane receptor Notch1 has recently been implicated in the specification of the T cell fate. In this review, we will discuss the role of Pax5 and Notch1 in the determination of lymphoid cell fates.

Section snippets

B-lineage commitment depends on the transcription factor Pax5

B-lymphopoiesis is an attractive system in which to examine the process of lineage specification, as its early stages have been relatively well characterized by the expression of cell-surface markers, the rearrangement status of the immunoglobulin heavy chain (IgH) locus and the requirements for growth factors 4, 5. Moreover, three different transcription factors have been identified by gene targeting to play essential roles in early B cell development (Figure 1). The basic helix–loop–helix

Coordinate activation of B-lymphoid-specific gene expression by EBF and E2A

The analysis of Pax5−/− pro-B cells has revealed that B-lineage commitment is determined neither by immunoglobulin DHJH rearrangements nor by the expression of E2A, EBF, λ5, VpreB, Igα and Igβ 14••, 15••. Instead, Pax5 seems to control this commitment process. Furthermore, the normal expression of E2A and EBF in Pax5−/− pro-B cells [11] indicates that these two transcription factors act upstream of Pax5 during B cell development in the bone marrow and thus cannot be directly involved in

Stochastic activation of Pax5 at the onset of B cell development

A long-standing debate concerns whether lineage commitment in the hematopoietic system occurs in a cell-autonomous, stochastic manner or whether it is controlled by instructive signals from the local environment 27, 28. With regard to B-lineage commitment, this question can be rephrased to ask how Pax5 transcription is initiated at the onset of B-lymphopoiesis. Unfortunately, extensive transgenic analysis has not yet resulted in the identification of a B-cell-specific control region of Pax5 [29]

Notch signaling is essential for specification of the T cell fate

In contrast to the generation of most hematopoietic cell types in the bone marrow, T cell development takes place in the thymus. T-lymphopoiesis is maintained at this extramedullary site by the continuous seeding of bone-marrow-derived progenitors, which differentiate within the thymic microenvironment into distinct thymocyte subpopulations [36]. Compared with early B-lymphopoiesis, little is known about the transcriptional control of early T cell development despite the fact that distinct

Conclusions

The functional analyses of transcription factors involved in early B-lymphopoiesis and the studies of Notch1 signaling in early T cell development are consistent with the following model for lineage commitment in the lymphoid system. This model (Figure 3) is based on the assumption that early lymphoid progenitors already express Notch1, but are not yet stimulated by Notch ligands in the bone marrow environment. In the absence of Notch signaling, these uncommitted progenitors are therefore able

Note added in proof

The paper referred to in the text as (D Eberhard, M Busslinger, unpublished data) has now been accepted for publication [60].

Acknowledgements

We thank P Pfeffer for a critical reading of the manuscript. This work was supported by the Institute of Molecular Pathology (Vienna) and the Basel Institute for Immunology.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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