regulation of lineage commitment during lymphocyte development

Inwrn. RPI, . lmn~~iriol., Vol. 20. pp. 45 64 Reprints available directly from the publisher Photocopying permitted by license only

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Regulation of Lineage Commitment during Lymphocyte Development FRANK JT. STAALa,* and HANS C. CLEVERSb

aDepartment of Immunology, f rasmus Univers/ty Rotterdam, Netherlands; 'Department of Immunology, Utrecht University, Netherlands

INTRODUCTION

B and T lymphocytes develop from pluripotent hematopoietic stem cells through a complex differentiation pathway involving many different phenotypically distinct subpopulations [ 11. During determination for and differentiation into a certain lineage, unique regulatory programs are established that direct cell type specific patterns of gene expression. This irreversible differentiation into a specific cell type is referred to as commitment. During commitment, a stepwise narrowing of the developmental potential occurs, while at the same time lineage- specific genes are being expressed. A program of cell type specific gene expression is established through interactions between the cellular micro-environment via cytokines and adhesion molecules, and endo- genous signaling molecules and transcription factors. Here we will review the signals and transcription factors that play a role in estab- lishing commitment towards the T and B cell lineage.

*Corresponding author.

45

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46 F.J.T. STAAL A N D H.C. CLEVERS

THE PARADIGM OF COMMITMENT DURING DEVELOPMENT: MYOGENESIS

In recent years, our understanding of the molecular events underlying myogenesis has increased considerably [2]. Muscle differentiation is preceded by several steps during which mesodermal precursor cells are specified. Markers of myogenic specification are MyfS, myoD, MRF4 and myogenin, which encode transcription factors of the basic helix- loop-helix family (bHLH) [3,4]. These factors bind to promoters of many muscle-specific genes and compose a regulatory pathway that establishes myoblast identity and controls terminal differentiation. When introduced into non-muscle cell types, each of these factors can activate the entire program for skeletal myogcnesis. The myogenic bHLH factors rely on a co-factor to activate muscle gene transcription, which is supplied by MEF2 (myocyte enhancer binding factor-2) [ 3 ] , belonging to the MADS box transcription factors. Thus, a network of interacting transcription and co-factors determines muscle-specific gene expresssion.

Signaling events leading to ni yogenic precursor cell specification and to the activation of the transcriptional activity of the above mentioned factors are being elucidated. Inductive signals emanate from the neural tube, notochord and ectoderm [S]. They include soluble factors such as basic fibroblast growth factor, insulin-like growth factor, and nerve growth factors, which do not induce muscle-specific differentiation, but rather help in the survival of developing myoblasts. I t is not yet completely clear how these factors couple to induction of transcription factor activity. Although this review is not about myogenesis, we can learn some lessons from muscle development, which are relevant for lymphocyte differentiation:

1. Combinations of transcription factors and cross-regulatory networks determine lineage-specific cell fate.

2. There is a hierarchy of transcription factors, and some lineage specific factors can already be expressed early on in multipotent precursor cells.

3. Lineage-associated growth factor receptors can help in the proliferation of a particular cell type. Often these growth factors are not

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8 A N D T CELL COMMITMENT 47

directing commitment per se, but function as survival factors for a lineage.

4. Inductive signals can arrive from outside the cell in a cell-specific microenvironment, but also long before precursor cells have reached the niche where they develop into lineage-restricted cell types.

OVERVIEW OF HEMATOPOIESIS AND LYMPHOCYTE DEVELOPMENT

Hematopoietic stem cells (HSC) in both man and mouse can be found in early embryonic development in the yolk sac, aorta-gonad-mesone- phros (AGM) region, fetal liver and bone marrow [6]. This is roughly the temporal order of appearance of HSC, although there is a clear difference in HSC that give rise to embryonic hematopoietic cells and HSC that can function as adult repopulating stem cells.

HSC can develop into several lineages including granulocytes (basophils, eosinophils, neutrophils), erythrocytes, megakaryocytes/ thrombocytes, monocytes/macrophages, lymphocytes (T, B, NK), both lymphocyte- and myeloid-derived dendritic cells and probably endothelial cells [7,8]. Besides these multiple choices, there are also multiple pathways that can lead to one cell type (for instance it has been suggested that B lymphocytes can develop from a common lymphoid stem cell, but also from a bipotent B cell/macrophage precursor [9,10]). Thus, it is difficult to strictly separate all lineages and present one developmental program for each cell type. In fact, two fundamentally different views on lymphoid development are currently put forward. The traditional view holds that lymphocytes arise from a common lymphoid stem/progenitor (CLP) cell, which arose from a HSC. B cells develop from this cell type in the bone marrow (BM) and T cells in the thymus, even though extra-thymic T cell development in other organs (e.g., the gut) is possible as well. The alternative view states that HSC differentiate into common B/T/myeloid precursor cells, which split off into pre-T/myeloid and pre-B/myeloid precursor populations. Thus, in this model, T and myeloid cells are more closely related than B and T cells. This model is discussed extensively in the chapter by Katsura and Kawamoto.

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48 F.J.T. STAAL AND H.C. CLEVERS

T and B cell development are very similar in many respects. The hallmark of B and T cell development is the recombination of immunoglobulin (Ig) and T Cell Receptor (TCR) genes via the action of the Recombinase Activating Genes (RAG)- ] and -2. During T cell development, cells branch off into common ap TCR bearing cells (a/) T cells) and the more rare yS T cells. Later in development there is another branchpoint into CD4 and CD8 T cells.

Although commonly used phenotypic markers may be different between human and mouse T and B cell development, virtually ident- ical differentiation stages can be discerned. In addition, rearrangement processes occur at the same stages in the same order. As far as we can tell, comparing data from immunodeficient patients and mutant mice, the same signaling molecules and transcription factors operate at the same stages of development. Thus, the major mechanisms governing murine and human lymphocyte development are conserved (Fig. 1 and Fig. 2).

In both the B and T cell lineage, multipotent cells differentiate into pro B/T cells where the first rearrangements occur (IgH D-J and TCRP DJ), followed by a pre BjT cell stage in which the first rearranged product is expressed on the cell surface together with a non-polymorphic chain (pseudo light chain for B cells; pre-T alpha for T cells). Thereafter the light chain (B cells) and alpha chain rearrange and are expressed on the surface as the mature BCR or TCR. Finally, B cells start to express IgD next to IgM and T cells differentiate after positive and negative selection into CD4 and CD8 single positive cells which leave the thymus.

REGULATION OF COMMITMENT TOWARDS THE LYMPHOID LINEAGE

Transcription factors are attractive candidates to regulate commitment towards lymphoid versus myeloid or T versus B cell lineage, because they are well-suited to regulate lineage-specific gene expression. Several transcription factors have been identified which, when specifically “knocked-out” through targeted mutation experiments, influence the development of all lymphoid lineages or the complete hematopoiesis. AML-1 is a transcription factor expressed in many hematopoietic

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B A N D T CELL COMMITMENT 51

cells, and knockout (KO) mice lack all mature blood cells, only fetal hematopoiesis is present [ l I] . A similar, but somewhat less severe phenotype is observed in mice lacking c-myb [ I 1,121. Pu.1 is a transcription factor that is expressed in B cells, myeloid cells, and early T cells and belongs to the Ets Winged Helix family of transcription factors [13,14]. Pu.1 mutant mice die perinatally due to macrophage and neutrophil loss, and lack B cells, stem cells and thymocytes; although T cell development recovers postnatally [14]. In that respect they are similar to Ikaros KO mice. Ikaros is a Zn finger transcription factor expressed in B, and T cells, but also in HSC and some myeloid precursors [15]. Mice with a true Ikaros null mutation have a block in B, NK and fetal T cell development, yet T cell development recovers postnatally [ 161. The original germline mutation in Ikaros [17] turned out to produce a dominant negative molecule that could not bind DNA, but could dimerize with other Ikaros family members, such as Aiolos and Helios [ 18-20]. It showed a much more severe phenotype, lacking all lymphocytes [ 171 and may therefore control development of common lymphoid progenitor cells (CLP) or commitment from HSC to lymphoid lineage. More information on the Ikaros family can be found in the chapter by Georgopoulos and colleagues in this volume.

Recent data support the existence of a bona fide CLP in adult murine bone marrow (BM) [21], although data from Katsura's group present an alternative view, which is extensively reviewed in another chapter of this volume. Specifically, single Lin-Scall"c-kit'"IL-7Rt BM cells were demonstrated to give rise to T, B, and natural killer (NK) cells, but to lack myeloid differentiation capacity. These cells are not self-renewing stem cells, but progenitors that have a limited life span [21]. HSC do not express IL-7R, and the upregulation of the IL-7R occurs at the stage of common lymphoid progenitors. The IL-7R mediates signals to reinforce the survival of developing T cells 1221, and to promote rearrangement of Ig heavy chain genes (IgH) in B-cell progenitors [23]. Thus, expression of the IL-7R is a critical step in the initiation of lymphoid development from HSC. However, I17-/- and Il7Rck-/- mice do not have an absolute block in lymphoid development, although they have much smaller numbers of progenitors in BM and thymus [24,25]. In B cell development, there are indications that IL-7 may help induce Ig recombination, but it is not likely to act as a

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commitment factor for B cells, since it also plays a role in T cell development. Other cytokines, such the c-kit ligand Stem Cell Factor (SCF) and Flt-3 ligand (FL) [26,27] also play a role in survival and proliferation of HSC and early lymphoid progenitors. Whereas mice deficient in flt3-receptor expression have normal numbers of all mature cell lineages, they have a selective reduction in the number of pro and preB-cells [28]. In addition, transplantation experiments with BM cells from FL-deficient mice also showed a defect in the T-cell compartment, indicating a role for FL and its ligand, in early lymphoid development [29]. Although specific lymphoid defects have not been reported in c-kit-deficient mice, this might be more difficult to show because c-kit-deficient mice have severe deficiencies in their stem cell pools. However, c-kit is expressed in the earliest stages of B- and T-cell progenitors as well as in CLP [26,27]. The prevailing view is that these factors act in synergy to promote proliferation of early progenitor cells, but are not inducing commitment. Support for this notion comes from studies with HSC lacking the survival gene bcl-2 [30]. These cells give rise to niyeloid and erythroid progeny, but not to lymphocytes. SCF, IL-7 and FL may work in a similar fashion to help survival of committed lymphoid progenitors (comparable to some of the growth factors in myogenesis). Indeed, mice lacking both the common gamma chain (used by several cytokines, including 1L-2 and IL-7) and c-kit have an almost complete block in thymocyte development due to lack of survival signals in the pro T cell stage [31]. Concluding, none of these three cytokines (IL-7, SCF, FL) act as factors that induce commitment towards the lymphoid lineage, although factors that induce expression of the IL7-R might be good candidates for such a commitment factor.

6 LYMPHOCYTE DEVELOPMENT (SEE FIGURE 1)

As stated above, transcription factors expressed specifically in a certain lineage and in turn needed for the expression of lineage specific target genes, are logical candidates for inducing commitment. Also, signals inducing or regulating activity of such transcription factors may act as commitment factors. However, for most transcription

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B AND T CELL COMMITMENT 53

factors important for T and B cell differentiation we do not know the signaling routes controlling their activities.

Loss of any of four transcription factors causes block in early stages of B cell development. These are E2A and the related factor E2-2 (or better: the E2A gene products El2 and E47 which arise through alternative splicing), EBF, Pax5 and Sox-4. E2A KO mice have the earliest B cell defect, but in these mice T cell development also is affected [32,33]. E2A belongs to thc basic-helix-loop-helix (bHLH) family of transcription factors and is not B cell specific in its expression. The most prominent feature of the E2A KO mice is, however, a complete block at the pro B cell stage. There is no expression of RAG- 1 or RAG-2, nor expression of A5 and VpreB, structural components of the pre-BCR, nor of the BCR signaling molecule Ig-cy (mb-I, CD79a). In addition, there are no sterile IgM transcripts, which nor- inally arise from the Ip intronic enhancer and make the Ig locus accessible for rearrangement. Moreover, expression of EBF and PAX5 is diminished, showing that a hierarchical, cross-regulatory network exists between these transcription factors, as we have introduced above for muscle development.

The E2A gene products, El2 and E47, are alternative splice forms that can both bind to DNA binding sites (E-boxes) in E2A target genes. They are non-redundant because B cell development in mice expressing El2 but lacking E47 is perturbed at the pro-B cell stage [34], and these mice lack IgM+B220+ B cells in both bone marrow and spleen. Thus, both El2 and E47 allow commitment to the B cell lineage and act synergistically to promote B lymphocyte maturation [34].

EBF mutants have a block in B cell development at almost the same stage [35] , but in contrast to E2A KO mice still express TdT (terminal deoxynucleotidyl transferase), which can insert nucleotides between recombining gene segments of Ig and TCR genes to generate addi- tional diversity. EBF null cells also show strongly reduced Pax5 expression [35].

The Pax5 gene locus encodes a protein termed B-cell-specific activator protein (BSAP) and is expressed, at least within the haematopoictic system, exclusively in the B-lymphoid lineage. Pax-5 is required in vivo for progression beyond the pro-B-cell stage [36], in that initial DJ IgH rearrangement is unaffected in Pax5 null mice, but transcription across the V genes to generate a fully rearranged VDJ segment does

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not occur [37]. Pax5 levels in v i v o depend on IL7/IL7R signaling [37], making I17R required not only for survival and proliferation, but also for Ig rearrangement, as shown in I17Rtr KO mice.

However, Pax5 is not essential for in vitro propagation of pro-B cells in the presence of interleukin-7 and stromal cells 1381. Very surpris- ingly, Pax5-/- pro-B cells have characteristics of HSC, despite the presence of rearranged DJ IgH genes. When stimulated with the appropriate cytokines, Pax-5-/- cells differentiate into functional macrophages, osteoclasts, dendritic cells, granulocytes and natural killer (NK) cells [38]. In the context of a thymus, they can even develop into T cells [39]. Pax5-/- pro-B cells express genes of several different hematopoietic lineages and, and restoration of Pax5 by retroviral transduction into P a - / - fetal liver cells represses this lineage- promiscuous transcription [38]. Thus, Pax5 can be regarded as a commitment factor for B cell development by suppressing developmental choices into other (non-B) lineages [38,40,41]. More information on Pax5 can be found in the chapter by Rolink and colleagues in this volume.

During murine embryogenesis, the transcriptional activator sox-4 is expressed at several sites, but in adult mice expression is restricted to immature B and T lymphocytes [42]. sox-4 KO mice die around El4 because of heart defects, precluding direct analysis of B and T cell development in these mice [42]. However, lethally irradiated mice can be reconstituted with SOX-4-/- fetal liver cells and show a block in B-cell development at the pro-B cell stage. In addition, the frequency and proliferative capacity of IL-7-responsive B cell progenitors in fetal liver were severely decreased. Since Sox-4 also influences T cell development [43] (see below), it is unlikely that s o x 4 can act as a commitment factor for B cell development.

Although signals that may induce transcriptional activity of these factors remain largely elusive, there are some indications that signals via the Notch1 receptor may influence E2A activity during B and T cell development [44]. In addition, upon activation of primary mature B lymphocytes via the BCR, both E2A protein levels and DNA-binding activity are induced [45]. E2A appears to be required to promote Ig class switch recombination [45]. However, although E2A activity is influenced by BCR (and maybe pre-BCR?) signaling, such signals come too late in development to influence commitment.

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T LYMPHOCYTE DEVELOPMENT (SEE FIGURE 2)

Mice with a targeted mutation in two different transcription factors, GATA-3 and Tcf-1 are known are known to specifically inhibit T cell developmcnt, while B cell differentiation is unaffected. Of these GATA-3 has the more severe phenotype. GATA factors (GATA-I, GATA-2, GATA-3) are Zn finger transcription factors which all play a role in regulating heniatopoictic gene expression [46 481. Mice with a germline mutation in GATA-3 die early in embryonic development, probably because it plays an essential role in other tissues, such as brain, kidney and adrenal glands, were it is highly expressed [49]. Using RAG-/- blastocyst complementation, it was shown that GATA-3 deficient ES cells contribute normally to erythroid, myeloid, granulocytic and importantly B cell linaeges, but not at all to the T cell lineage [50]. There was no contribuation of thc ES cells to even the earliest stages of thymocyte development [50]. In accordance with this, chimeric mice generated by injection of GATA-3-deficienL LacZ- expressing ES cells into wild-type blastocysts, contained no [%galacto- sidase expressing thymocytes [51]. In the LacZ “knock-in” mice, no contribution of GATA-3-deficient cells to the T cell lineage was detected, not even in the earliest CD44+CD2S-doubIe-negative-l (DNI) stagc in the thymus [51]. Analyses of fetal liver, bone marrow and AGM regions has not been donc on these mice. Therefore, it is unclear if very early thymocyte development and T cell commitment, or development of a n even earlier cell type or migration and homing to the thymus arc affected. Nevertheless, GATA-3 remains a good candidate for a commitment factor for the T cell lineage.

Another candidate T ccll commitment factor is formed by the T cell specific protein Tcf-I. Tcf-1 is part of a family of proteins containing an HMG-box as the DNA-binding domain [52-56]. A closely related family member is Lef-1, which is present not only in T cells, but also in immature B cells [55]. Disruption of Tcf-1 results in a block in T cell development at the ISP to DP transition [57] and within the DN compartment at the CD44+CD25- to CD44+CD25’ transition [58]. Importantly, cells in the DN2 and ISP stage arc apparently not pro- liferating [%]. Thymocyte development is not completely blocked because of the compensatory role of Lef-1. Indeed Tcf-1/Lef-l double KO mice show complete block in T cell development in fetal thymic

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organ cultures at the ISP stage and a marked inhibition at the DNI and DN3 stage of development [59,60]. Remarkedly, in 4-6 month old Tcf-l null mice, thymocyte development is completely blocked at the DNI stage. Moreover, Tcf-l KO bone marrow stem cells can give rise to all hematopoietic lineages except T cells in radiation chimeras ([%I, Staal, Meeldijk and Clevers, unpublished observations). Taken together, Tcf-1 is required for the earliest stages of adult T cell development; but in fetal thymopoiesis its requirement is less stringent.

Tcf-l is not an active transcription factor by itself, but requires the interaction with the Wnt effector P-catenin [61]. It is unknown which signal transduction routes control Tcf-dependent transcription, but they are likely to act by ultimately providing [kitenin in the nucleus to interact with its partner Tcf-1 to activate target genes. Signals operating on DN thymocytes, such as the preTCR and the cytokines IL-7 and SCF do not activate Tcf-dependent transcription [62].

/]-catenin is a known component of the Wnt signaling cascade [63]. Wnt proteins constitute a large (> 19 members) family of extracellular signaling molecules that are found in many different species and influence cell fate and cell behavior during development. Among the best- studied effects of Wnts are the determination of segment polarity in Drosophilri and the specification of the body axis in X m o p u s (reviewed in [63]). Deregulation of Wnt signaling has been shown to occur in several human cancers, through mutations in key molecules of the Wnt pathway, including ,&catenin. Wnts function as ligands for members of the Frizzled (Fz) family of serpentine receptors. Wnt binding to Fz initiates a complex signaling cascade that culminates in nuclear trans- location of k a t e n i n , which can then interact with niembcrs of the Tcf/Lcf family to activate transcription of target genes [64 661. A recent study has shown that Wnts can activate Tcf-controlled transcription in thymocytes, and subsequently, that Wnt signals are required for normal T cell dcveloprnent (Staal rt d., submitted). Thus, the signaling route for a transcription factor involved in T-lymphoid development has now been identified.

Thc importance of Tcf-l and GATA-3 in T cell development is underscored by a study in which these transcription factors were studied simultaneously. Tcf- I and GATA-3 protein can already be detected in DNl cells and throughout thymic development [67]. In DN 1 cells, the production of Tcf- 1 is immediately followed by intra-

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cellular expression of CD3 epsilon. Moreover, T cell development from fetal liver cells, but not fetal thymus progenitors in fetal thymic organ culture systems, is severely inhibited by the addition of antisense oligonucleotides for either Tcf- I or GATA-3 [67]. These results strongly suggest that Tcf-1 and GATA-3 play essential roles in the initiation of the earliest steps of T cell development in the thymus. Thus, both may function as commitment factors for T cell development, although the incomplete block in T cell differentiation in Tcf-1 null mice argues against Tcf-1 being a dominant factor in this respect.

Several other transcription factors (such as Sox-4, Ets-1 and 6EF1) 143,681 may play a role in regulating thymic cellularity, but probably control survival and proliferation of developing thymocytes, rather than T lineage commitment.

One class of transcription factors should be mentioned here, because these proteins may regulate differentiation into either the N K or T cell lineage in D N I and D N 2 cells (DN3 cells are fully committed to beconic T cells). These are the inhibitory bHLH factors of the Id family (Idl, Id2, Id3, ld4) [69], which lack D N A binding activity and can dimerize with for instance E2A and the more T cell specific HEB bHLH protein [70]. Since E-box bHLH proteins play an important role in initiating rearrangement of Ig and TCR genes, it is not surpris- ing that inhibiting this activity can push cells more into the NK lineage (71,721. Indeed Id1 overexpression can inhibit E2A function and inhibit B cell development. Id2 null mutant mice have a markedly reduced number of NK cells, but normal T cells [73]. Overexpression of Id3 inhibits thymocyte development, but not NK development in vitro [74]. Thus, Id proteins may help regulate commitment towards the N K cell lineage in cells that can become T. N K or dendritic cells. I t remains to be elucidated which of the four Id genes play a role in this decision and how their activity is regulated.

NOTCH GENES AS EFFECTORS OF DIFFERENTIATION

Notch genes encode a highly conserved family of transmembrane receptors that regulate the progression of cells from an undifferen- tiated to a diffcrentiated state as well as the cell fate decisions made at branchpoints between distinct developmental pathways (reviewed in

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[75]). Four mammalian Notch homologs (Notch14) have been identified. Mammalian Notch signaling is initiated by binding of one of a series of ligands that are also transmembrane proteins, such as Jaggedl, Jagged2 or Delta. Ligand binding leads to a series of proteolytic cleavages resulting in transport of the intracellular domains of Notch to the nucleus, where Notch behaves as a transcriptional activator [75]. One important downstream target of Notch is a transcription factor, called Suppressor of Hairless in invertebrates and CBFI/RBP-J in vertebrates [75]. The targets of activated CBFI/ RBP-J are incompletely characterized but include the Hairy Enhancer of Split (HES) genes, which are upregulated by Notch and which in turn downregulate the activity of certain bHLH transcription factors. HES-1 binds to the CD4 silencer and can repress CD4 expression [76], and may therefore regulate choice between CD4 and CD8 fates. A role for Notch1 signaling in this binary cell fate decision, is suggested by in vivo results in which Notch 1 transgenic expression influences CD4 versus CD8 T cell fate [77].

Inducible Notch-l KO mice using the crellox recombination system have been constructed. When Notch was deleted in BM and thymus, T cell development was blocked at the DNI stage, with B220 positive cells developing in the thymus, a feature often observed when T cell development is severely impaired [78]. Moreover, retroviral transduction of constitutively active Notch-I, N'", into murine bone marrow precursors results in the development of CD4'CD8+ DP T cells in the bone marrow (which eventually develop into tumors) and completely prevents B cell development [44]. Thus, lymphoid precursor cells develop into T cells via Notch signalling, but in absence of such signals choose ii B cell fate. Notch signals may function by inhibiting E2A activity, as Notch signals have been shown to shown to block activation of a E2A-regulated promoter [44,76]. Indeed the phenotype of the E2A-/- mice is very similar to the phenotype of mice derived by overexpression of activated Notch- 1 in bone marrow precursors. Interestingly the Notch target HES-I is needed for early T cell development [79,80]. In Hes-I-/- mice, T cell development is arrested in the DNI stage, similar to the mice with conditional inactivation of

Notch signals influence ii variety of other processes, including the maintenance of a pool of less differentiated cells (CD34+ HSC),

Notch-1 [79,80].

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preventing apoptosis [81], the maturation of TCRf T cells [82], the development of CD8+ cells from DP cells [82], and probably negative selection in the thymus [82-841. How exactly these very diverse developmental choices are regulated by Notch signaling and which transcriptional activators and repressors are being used, is currently unclear. However, i t is now well-documented that Notch can regulate lineage choice between B and T cell fates, as described above.

CONCLUDING REMARKS

A large group of soluble factors, signaling molecules and transcription factors regulate the fate of cells at the earliest stages of T and B cell differentiation and commitment to the lymphoid lineages. For the regulation of the latter step, members of the Ikaros family play an important role. Many studies have focussed on the role of transcription factors in B vs. T lymphoid commitment, but one master regulator gene controlling B or T cell development by activating transcription of lineage specific target genes, has not been found. Rather, signals that suppress alternative lineage choices seem to provide strong signals. For instance, Pax5 signals in non-B cells and Notch signaling suppressing E2A activity in developing thymocytes. On the other hand, a com- bination of positively acting factors may constitute a commitment factor network. Alternatively, some of the positively acting factors may not have been identified yet. It is also clear that many different signaling routes integrate to decide the outcome of the many choices faced by lymphoid precursor cells. For example, DN thymocytes are influenced by Notch, Wnt and cytokine signaling and by signals via the prc TCR. How such signals operate together to control development into a certain lineage and survival of that cell type, is going to be a likely subject of extensive, future research.

Acknowledgments

We thank Dr. T. Langerak for critical rending of the manuscript and Dr. R. Hendriks for useful suggestions. FJTS is a fellow of the Dutch Royal Academy of Sciences (KNAW).

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regulation of lineage commitment during lymphocyte development

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