the function of e- and id proteins in lymphocyte development

© 2001 Macmillan Magazines Ltd

The development of B cells in the bone marrow and T cells in the thymus have each been defined in termsof the expression of several temporally regulated pro-teins that serve as developmental markers (FIG. 1).Although there is little overlap in the markers definedfor developing mouse B and T cells, the two develop-mental pathways have several analogous features. Afterinitial commitment to a T- or B-cell fate, both classes oflymphocyte have to pass two main developmentalcheckpoints to progress to maturity1,2. Passage througheach of these checkpoints depends on successfulrearrangement of the genes that encode the variablecomponents of their respective antigen receptors.The first of these checkpoints tests for expression ofeither the immunoglobulin heavy chain for B cells orthe T-cell antigen receptor (TCR) β-chain for αβ T cells.Productive rearrangement of these genes allows for theassembly of an immature receptor complex that trig-gers the differentiation and proliferative expansion ofprecursor lymphocytes. Subsequently, these pre-B andpre-T cells cease proliferating and initiate rearrange-ment of either the Igκ or Igλ light chain (B cells) or theTCRα chain (T cells). Passage through the second check-point again requires an in-frame rearrangement event toallow for expression of a mature B-cell receptor or TCR.Final maturation is also dependent on the affinity ofthese antigen receptors for self-antigen, as potentially

autoreactive lymphocytes are eliminated, ANERGIZED, or, inthe case of B cells, undergo receptor editing. In addition,prospective mature T cells need to be positively selectedon the basis of a low-level affinity for self-peptidesbound to major histocompatibility complex (MHC)molecules on thymic antigen-presenting cells.

The helix–loop–helix (HLH) family of transcrip-tion activators and repressors has been shown to beimportant in several developmental processes. HLHproteins have been subdivided into classes on thebasis of a number of structural and functionalcriteria3. Class I HLH proteins, which we will refer toas ‘E-proteins’, are transcription activators that bindDNA at E-box (CANNTG) motifs as homodimers orheterodimers with other HLH proteins. In manydevelopmental systems, the principal regulatory HLHcomplexes are composed of dimers between thebroadly expressed E-proteins and tissue-specific class IIHLH proteins, which can only bind DNA as hetero-dimers with E-proteins. However, in lymphocytedevelopment, E-proteins seem to operate primarily ashomodimers or heterodimers with other E-proteins3.The mammalian E-proteins are encoded within threeseparate genes, E2A, HEB and E2-2. These genes wereeach isolated in screens for proteins that could bind E-box sites found in enhancers, such as those for the immunoglobulin heavy and Igκ light chains4–7.

THE FUNCTION OF E- AND ID PROTEINS IN LYMPHOCYTEDEVELOPMENTIsaac Engel and Cornelis Murre

Helix–loop–helix proteins are essential factors for lymphocyte development and function. In particular, E-proteins are crucial for commitment of lymphoid progenitors to the B- and T-celllineages. E-proteins are negatively regulated by the Id class of helix–loop–helix proteins. The Idproteins function as dominant-negative inhibitors of E-proteins by inhibiting their ability to bindDNA. Here, we review the role of E-proteins and their Id protein antagonists in lymphocyteproliferation and developmental progression. In addition, we discuss how E-protein activity andId gene expression are regulated by T-cell receptor (TCR) and pre-TCR-mediated signalling.

ANERGIZED

A state of non-responsivenessto antigen.

NATURE REVIEWS | IMMUNOLOGY VOLUME 1 | DECEMBER 2001 | 193

Division of Biology, 0366,University of California,San Diego, La Jolla,California 92093, USA.Correspondence to C.M.e-mail: [email protected]

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observed in Pax5 null mice, these findings imply thatE2A is also necessary for B-cell commitment, at leastindirectly. This conclusion is also supported by studies inwhich E2A proteins were shown to induce the conver-sion of the bipotent 70Z/3 cell line from a macrophageinto a pre-B phenotype13. In this system, E2A proteinswere found to induce expression of Pax5, as well asearly B-cell factor (EBF), another transcription factorthat is essential for early B-cell development14. So, E2Aseems to lie upstream of both EBF and Pax5, in apathway that results in the initiation of the B-lineagedevelopmental programme.

The E2A gene is also important in the initial stages ofT-cell development. Thymocyte numbers in E2A nullmice are typically tenfold lower than those found inwild-type littermates15. The principal defect underlyingthe reduced thymic cellularity of E2A-deficient mice iswithin the most immature subsets of T-cell precursors,which are defined as double-negative (DN) as they lackexpression of the CD4 and CD8 co-receptor molecules.A disproportionately high percentage of E2A-deficientCD4–CD8– DN thymocytes fall within the most imma-ture subset, which can be defined on the basis of theexpression of high levels of CD44 and low levels ofCD25 (REFS 15,16). CD25–CD44+ (DN1) cells have been

Although the HEB and E2-2 genes encode severalpotential isoforms that can be generated through alter-native RNA splicing, the E2A locus directs the expres-sion of two proteins, E12 and E47 (FIG. 2). This reviewwill focus on the roles that have been identified for E-proteins in lymphocyte development, with emphasison the elucidation of some newly defined functions forE2A in the regulation of T-cell differentiation. Ratherthan discussing the role of E-proteins in lymphocytesin strict developmental order, we have organized thisreview to roughly follow the chronological order inwhich these discoveries were made.

E2A: an initiator of lymphocyte developmentTargeted mutations within the E2A locus have shownthat this gene is essential for the initial events in lympho-cyte differentiation. B-cell development in E2A-deficientmice is arrested at a very early stage, before the onset ofimmunoglobulin heavy-chain rearrangement8,9. Thesedata are particularly interesting in the light of studiesindicating that Pax5 (paired box gene 5), another tran-scription factor required for B-cell developmental pro-gression, is necessary for irreversible commitment to theB lineage10–12. Because B-cell development in E2A-deficient mice is blocked at an earlier stage than that

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Figure 1 | Schematic model of T-cell and B-cell development. a | T-cell development; b | B-cell development. Developmental stages are presented as labelledcircles, with the names of significant surface-marker molecules attached. The approximate points during which lymphocyte commitment, proliferation and antigen-receptor gene rearrangement are indicated by lines above the circles. The roles of E2A or HEB proteins are indicated in red. CLP, common lymphoid precursor; DN, CD4– and CD8– double-negative thymocyte; DP, CD4+ and CD8+ double-positive thymocyte; Imm. B, immature B cell; ISP, immature single-positive CD8+

thymocyte; pre-TCR, pre-T-cell antigen receptor; pre-BCR, pre-B-cell antigen receptor; SP, CD8+ or CD4+ single-positive thymocyte; TCR, T-cell receptor.

© 2001 Macmillan Magazines LtdNATURE REVIEWS | IMMUNOLOGY VOLUME 1 | DECEMBER 2001 | 195

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the T-/NK-cell-fate decision is highly influenced by thelevels of E-protein activity.

Although T-cell development is severely affected bythe absence of E2A protein, it is not completely blocked,as is the case for B cells. It should be noted that, whereasthe principal E-proteins expressed in the B-cell com-partment are encoded by E2A, thymocytes express highlevels of HEB, in addition to E2A proteins, and the prin-cipal E-box-binding complexes detected in T-cell linesand thymocytes consist of HEB/E47 heterodimers15,26,27.So, it is possible that HEB can partially compensate for adeficit in E2A. This idea is supported by the fact thatHEB transcripts can be detected in even the mostimmature thymocyte subsets22. Interestingly, it has beenshown that insertion of an HEB complementary DNAinto the E2A locus can rescue B-cell development inE2A-deficient mice, proving that HEB can assume manyof the functions of E2A proteins28. In addition, defectsin thymic development are observed in mice that areheterozygous for null mutations in both HEB andE2A29. However, the defects observed in HEB null thy-mocyte development occur later than those describedabove for E2A-deficient mice, involving primarily thetransition from the immature single-positive (ISP) tothe CD4+ and CD8+ double-positive (DP) stages29,30.Furthermore, it has been reported that the HEB cDNA‘knock-in’ does not rescue the thymic phenotype ofE2A-deficient mice30. Therefore, E2A and HEB havesome unique functions, at least at select points duringthymocyte development.

E2A proteins have been shown to regulate theexpression of several genes that are important in initiat-ing lymphocyte development. These include pre-Tα inT cells, EBF and Pax5 in B cells and the recombination-activating (RAG) genes in both lymphocyte lin-eages13,22,31,32. In addition, HEB and E2A proteins havebeen shown to induce germ-line immunoglobulin andTCR gene-rearrangement events when co-expressedwith the RAG1 and RAG2 genes in a non-lymphoid cellline, and to be required for TCR V to DJβ rearrange-ment33–35. The role of E-proteins in the induction of thepre-Tα gene, which encodes a component of the pre-TCR complex, has been further defined by two recentstudies that indicated the importance of E-box sites inthe activity of the pre-Tα promoter32,36,37. Both of thesestudies showed that mutation of two adjacent E-boxesin the pre-Tα promoter severely reduced transcriptionalactivity32,37. These reports also showed that ectopicexpression of E-proteins could enhance pre-Tα pro-moter activity, although they differed with respect to theeffect of exogenous HEB on the activity of pre-Tα pro-moter constructs. One of these studies found thatectopic HEB markedly increased pre-Tα promoteractivity37. However, the other report found thatalthough co-transfection of E12 markedly induced thepre-Tα promoter, exogenous HEB had a relatively smalleffect on promoter activity, and only in the presence ofectopic E12 (REF. 32). Furthermore, Reizis and Lederfound that E-boxes were not important for the activityof the pre-Tα enhancer, apparently contradicting theresults of a previous study showing that HEB could act

shown to have multipotent developmental potential andhave not initiated TCR-chain gene rearrangements17–19.The transition of thymocytes from the DN1 toCD25+CD44+ (DN2) and CD25+CD44– (DN3) subsetsis associated with the onset of TCR rearrangement andthe restriction of developmental potential towards theT lineage18–20. A recent report21 has indicated thatalthough DN1 cells express little or no E47 protein, DN2and DN3 cells contain uniformly high levels of E47.Similar upregulation of E2A mRNA between the DN1and DN2 subsets has also been observed22. Takentogether, these data imply that the induction of E2Aexpression in uncommitted thymocytes is necessary forefficient initiation of the T-cell developmental pro-gramme. It should also be noted that the defects in E2Anull DN thymocytes apparently affect more than thegeneration of αβ T cells, as development of the γδ T lineage in E2A-deficient mice is also severely perturbed23.

Additional evidence supporting a role for E-proteinsin the initiation of T-cell development comes fromstudies of the effect of a surplus or deficit of Id proteinson T- and natural killer (NK)-cell-lineage commitment.There are four vertebrate Id proteins, Id1–4, whichcomprise a class of HLH proteins that lack a DNA-binding domain, and can incorporate E-proteins intoE–Id heterodimers that are unable to bind E-boxsequences3 (FIG. 2). Therefore, the Id proteins can func-tion as negative regulators of E-protein activity.Overexpression of Id3 in uncommitted human lym-phoid progenitors has been shown to block the devel-opment of T cells and promote NK-cell developmentin reconstituted fetal thymic organ culture24. Theseobservations were later complemented by the findingthat NK-cell development and function are markedlyreduced in Id2-deficient mice25. These data indicate that

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Figure 2 | E- and Id protein structure and function. a | Schematic depiction of the E- and Idproteins, with the AD1- and LH (AD2)-activation domains and the basic (b) and helix–loop–helix(HLH) DNA-binding and dimerization domains highlighted. b | Illustration of how E-proteindimers bind E-box sites in promoters and enhancers, and activate transcription of targetgenes. Id proteins lack the basic domain required for DNA binding, so Id–E-protein dimers arethereby unable to bind promoters and activate transcription.


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pathway has been previously shown to be essential forpositive selection46,47. Additional data indicate that Id3transcription is induced through the activation of theMAP kinase-responsive transcription factor Egr1 (earlygrowth-response factor 1) (REF. 43). Taken together, thesedata support a model in which TCR ligation mediatesthe inhibition of E-protein activity, at least in partthrough an induction of Id3 initiated by activation ofthe RAS–ERK–MAP kinase cascade (FIG. 3).

E-protein regulation of the DN–DP transition The developmental progression of DN thymocytes tothe DP stage is dependent on assembly of a pre-TCRcomplex, which contains the pre-Tα chain togetherwith the β-chain and CD3 complex molecules that arealso found in the mature αβTCR. The similaritiesbetween the pre-TCR and αβTCR complexes indicatethat the DN–DP transition could also involve themodulation of E-box activity. Indeed, evidence to sup-port such a model comes from a recent study involvingthe stimulation of developmental progression in Rag-deficient mice21. Mice that lack Rag1 or Rag2 areunable to initiate antigen-receptor gene rearrange-ment, and consequently Rag-deficient thymocytes arearrested at the DN3 stage. However, injection of anti-bodies against the CD3 complex into mice with defects

positively on this enhancer22,37,38. These discrepanciesmight be due to differences in the cell lines and expres-sion and reporter constructs used by the differentgroups, and perhaps could be resolved by analysis of theappropriate transgenic reporter constructs in mice thatare deficient for either HEB or E2A.

E-proteins and thymocyte positive selectionThe E2A-deficient thymocytes that escape the block atthe DN1 stage show additional defects at later points inT-cell development. One phenotype shown by moremature E2A-deficient thymocytes is that of accentuatedpositive selection. E2A mutant mice show relatively highpercentages of mature, CD4 or CD8 single-positive (SP)thymocytes compared with wild-type littermates15.These observations could be explained by a generalincreased survival of SP cells relative to that of DP thy-mocytes, or by an increased tendency of E2A-deficientthymocytes to undergo positive selection. To distin-guish between these possibilities, E2A-deficient micewere bred onto backgrounds that contain transgenesfor either the HY TCR, which directs positive selectionto the CD8 SP lineage, or the AND TCR, which pro-motes the selection of CD4 SP thymocytes39,40. Analysisof these mice indicated that a deficiency in E2A pro-teins promoted specific positive selection, rather than ageneral increase in all SP thymocytes41. It has not yetbeen established that this positive-selection defect isintrinsic to E2A-deficient thymocytes. Regardless of theexact mechanism, these data indicate that E2A proteinsfunction to attenuate positive selection.

Additional evidence for a role of E-proteins in pos-itive selection came from analyses of the effects ofdeletion of the Id3 gene on thymocyte development.Id3-deficient mice were found to contain reduced per-centages of SP thymocytes42. Breeding Id3–/– mice ontotwo different TCR transgenic backgrounds showedpronounced defects in positive selection. Furthermore,the percentages of SP thymocytes were restored to nearnormal in mice that were deficient for both Id3 andE2A, which indicates that these proteins functionallyantagonize each other. So, modulation of E-box activityhas a crucial role in thymocyte positive selection.

Transfer experiments, in which Id3-deficient TCRtransgenic fetal liver cells were used to reconstitute irra-diated wild-type hosts, showed that the deficit in posi-tive selection in Id3–/– mice seems to be T-cell intrinsic42.From these data it can be inferred that TCR-mediatedsignals that initiate the positive selection of thymocytesprobably act to induce Id3, which, in turn, inhibits E-protein activity. Evidence for such a mechanism oper-ating in DP thymocytes has been recently provided43.Crosslinking of the TCR in DP cells in vitro inducesexpression of Id3 RNA and inhibits E-box DNA-bindingactivity. Furthermore, both the induction of Id3 andthe reduction of E-box binding are inhibited by anagent that blocks the activation of the mitogen-activat-ed protein (MAP) kinase kinases MEK1 and MEK2,which are kinases that are involved in signal transduc-tion through the RAS extracellular-signal-relatedkinase (ERK)–MAP kinase pathway44,45. This signalling

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Figure 3 | Inhibition of E2A by TCR signalling. Diagramdepicting the inhibition of E2A activity by T-cell receptor(TCR)-mediated activation of the RAS–ERK–MAP kinasepathway, inducing EGR1 and subsequently Id3 expression.(ERK, extracellular signal-regulated kinase; GRB, growth-factor receptor bound; MAP, mitogen-activated proteinkinase; MEK, MAPK kinase.)


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are likely to regulate later stages of B-cell development.For example, overexpression of Id3 in mature, activatedB cells acts to inhibit immunoglobulin class switching50.These data are consistent with observations that E2Aprotein levels and DNA-binding activity increases ontreatment of B cells with stimuli known to induce classswitching50. Furthermore, Id3 null mature B cells showproliferation defects that can be corrected by ectopicexpression of Id1 (REF. 51). Id3 has also been shown to berequired for the negative regulation of B-cell-progenitorgrowth and survival by transforming growth factor-β

in gene rearrangement or TCRβ-chain expression hasbeen shown to induce the rapid expansion of the thy-mocyte pool together with progression to the DPstage48,49. Rag-deficient thymocytes show a substantialdrop in E-box DNA-binding activity within hoursafter in vivo administration of anti-CD3. This decreasein binding is also associated with a marked inductionof Id3 RNA that is at least partially dependent on sig-nalling through the RAS–ERK–MAP kinase pathway.So, E-protein DNA-binding activity is negatively regu-lated by signalling initiated by both the pre-TCR andthe mature αβTCR.

The functional importance of the inhibition ofE-protein activity by pre-TCR signalling is indicated bythe effect of E2A-deficiency on T-cell development inmice with defects in TCR rearrangement21. A deficiencyin E2A proteins was found to completely abrogate thedevelopmental block normally observed in Rag1 nullmice, allowing progression to the DP stage, and occa-sionally to the CD8 SP stage as well. DP thymocytes areoften even observed in Rag-deficient mice that are het-erozygous for the E2A mutation. The developmentalarrests normally observed in SCID MUTANT or TCRβ nullthymocytes are also abrogated by a deficiency in E2Aproteins (REF. 21, and I. E. and C. M., unpublished obser-vations). Furthermore, E2A proteins are required for thedevelopmental block in thymocytes that is derived fromRag-deficient bone marrow transferred into an irradiatedE2A wild-type host, indicating that E2A proteins func-tion at this stage in a bone marrow-intrinsic manner.Therefore, E2A has an essential role in enforcing thedevelopmental arrest of thymocytes with defects thatprevent TCRβ expression. These data, when takentogether with the other studies described above, showthat E2A proteins act to regulate several stages of T-celldevelopment (FIG. 4).

The roles of E-proteins in T-cell development shouldalso be examined in the context of recent data regardingthe relative levels of E47 protein in DN, DP and SP thy-mocytes21. E47 is expressed at relatively high levels fromthe DN2 until the DP stage, when the levels are signifi-cantly reduced. The transition to the mature SP stage isaccompanied by a further drop in E47 protein levels.So, a gradient of E47 protein levels is expressed through-out T-cell development. The reduction in E47 proteinbetween the DP and SP stages is consistent with the dataconcerning the role of E-proteins in positive selection.However, a complete analysis of the relationship of theregulation of E47 levels to E-protein activity and func-tion in the T-cell lineage has yet to be completed. It willalso be important to examine whether similar E47expression gradients exist in the B lineage.

E-proteins at later stages of B-cell developmentBecause the block in B-cell development found in E2Anull mice is complete, and as no conditional knockoutmice that target E2A expression in the B-cell lineage areavailable, it has not been possible to study directly theeffects of E2A deficiency in committed B-lineage cells.Studies carried out in the context of either a deficit orsurplus of Id proteins, however, indicate that E-proteins

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A naturally occurring mousemutant with severe combinedimmune deficiency, due to aninability to rearrange antigen-receptor chain genes.

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Figure 4 | Model that outlines the role and regulation ofE2A during T-cell development. E2A proteins act topromote the initial stages of T-cell development, includingcommitment to the T lineage, but inhibit both the double-negative (DN) to double-positive (DP) transition and thepositive selection of DP thymocytes. Signalling from theantigen receptor acts to inhibit E2A protein activity and allowfurther developmental progression. SP, single-positive; TCR,T-cell receptor.


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activated in different lineages and developmentalstages. Alternatively, it is conceivable that a gradient ofE-protein activity might act to regulate cell growth andsurvival, with either very high or low activity levels ini-tiating processes that lead to growth arrest and/orapoptosis. Distinguishing between these hypotheseswill probably require a detailed molecular characteriza-tion and comparison of the pathways leading to apo-ptosis and cell-cycle inhibition that can be triggered byeither high or low levels of E-protein activity.

Concluding remarksIn summary, E-proteins have been implicated in theregulation of several stages of the development of bothB and T lymphocytes. A role for E-proteins in lymphoiddendritic cell development has also been described (BOX 1). It is likely that other roles remain to be discov-ered. In particular, it will be interesting to explore theroles of E-proteins in the checkpoints coupled withantigen-receptor rearrangement in B cells, to testwhether there are parallels between the functions ofE-proteins at analogous points in B- and T-cell devel-opment. In addition, the roles of HEB proteins in thy-mocyte positive selection and the DN–DP transitionneed to be carefully examined and contrasted with thatof E2A. Another important challenge will be to definethe mechanisms by which E-proteins regulate lympho-cyte development. This will require not only the identi-fication of all of the crucial target genes, but also thecharacterization of the mechanisms by which E-proteintargets are regulated in a lineage and stage-specific man-ner, such that their expression is limited to the appropri-ate developmental context. This will probably involvedetailed analyses of the promoter and enhancer ele-ments that regulate expression of the relevant targets.Furthermore, a complete understanding of how E-pro-teins function in lymphocyte development might haveto include additional studies of the mechanisms bywhich E-proteins can be regulated. For example, reportsindicate that E-protein transcriptional activity and DNAbinding can be modulated by phosphorylation57–59.There are also studies suggesting that E2A activity mightbe modulated by Notch signalling (BOX 2). It will beinteresting to see if E-proteins are differentially phospho-rylated during lymphocyte development, and if phos-phorylation or other modifications have any role in theregulation of E-protein activity in the T and B lineages.

(TGF-β)52. The induction of Id3 by TGF-β is depen-dent on signalling through the SMAD FAMILY of transcrip-tion factors; therefore, identifying a second pathway inaddition to the RAS–ERK–MAP kinase cascade bywhich extracellular signalling can regulate Id3 levels53.These data indicate that E-proteins and their inhibitorsregulate survival and proliferation at several points inB-cell development.

Lymphocyte proliferation and survivalMany of the effects of E-proteins on lymphocyte devel-opment are likely to relate to their impact on growthand survival. It is interesting to note, however, that E-proteins have been implicated in both the promotionand inhibition of cell survival and growth at differentpoints in lymphocyte development. For example, Id3 isrequired for the induction of growth arrest and apopto-sis in B-lymphocyte progenitors by TGF-β; however,E2A proteins act to prevent the inappropriate expan-sion of DN thymocytes21,52. Furthermore, ectopic E2Aexpression has also been shown to induce apoptosis inT-lymphoma lines; however, Id overexpression canpromote apoptosis in both thymocytes and B-cellprogenitors52,54–56. These opposing activities could per-haps be explained by differences in the target genes

SMAD FAMILY

Transcription factors that areactivated by TGF-β signalling.

NOTCH SIGNALLING

A signalling system comprisinghighly conservedtransmembrane receptors thatregulate cell-fate choice in thedevelopment of many celllineages, including lymphocytes.

Box 1 | E-proteins and dendritic cell development

Dendritic cell (DC) populations have been shown to originate from both myeloid and lymphoid progenitorpopulations17. In particular, a thymic DC population has been defined that can be derived from DN2 cells, andthymic DCs have been reported to express pre-Tα mRNA20,66. So, lymphoid DCs can be derived from a populationthat expresses high levels of E2A proteins, as well as at least one regulatory target of E2A and HEB. It has recentlybeen shown that overexpression of Id2 and Id3 in fetal liver precursors blocks the development of lymphoid, butnot myeloid, DCs67. Therefore, E-proteins seem to have an essential role in the development of lymphoid DCs aswell as B and T cells. Furthermore, the data imply that although E2A proteins are necessary for efficientcommitment to the T-cell lineage, it is likely that there are factors that act after the onset of E2A expression toregulate the generation of DC and T-cell precursors. It will be interesting to define the vital determinants thataffect the T/DC fate decision in the thymus.

Box 2 | E-proteins and Notch signalling

Several lines of evidence now implicate the NOTCH SIGNALLING pathway as an importantregulator of lymphocyte development, and the T- versus B-lineage decision inparticular60. Notch is required for the generation of committed T-cell precursors in thethymus and, in the absence of Notch, thymocytes assume a B-cell developmental fate61.Conversely, ectopic Notch activity in the bone marrow blocks B-cell development andresults in the generation of double-positive T cells62. Notch signalling is initiated by theinteraction of Notch receptors with ligands of the Delta family, which triggers therelease of the Notch intracellular fragment (Notch-IC) from the Notch receptorcomplex60. Among its many activities, Notch-IC has been reported to repress theactivity of E2A proteins62,63. The repression of E2A protein activity by Notch signallingis consistent with the fact that an increased ratio of mature CD8 to CD4 single positiveT cells is observed in both E2A-deficient and at least some Notch-IC transgenicbackgrounds15,64. However, it must be noted that ectopic Notch-IC activity, unlike adeficiency of E2A proteins, cannot drive T-cell development past the DN3 stage in Rag-deficient mice21,65. Furthermore, the importance of both E2A protein expression andNotch activity in the earliest stages of T-cell commitment is not compatible with thesimplest models that involve the repression of E2A activity by Notch signalling. So, it isnot yet clear whether the inhibition of E-protein activity by Notch-IC is an importantfactor in lymphocyte development.


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Online links

DATABASESThe following terms in this article are linked online to:LocusLink: http://www.ncbi.nlm.nih.gov/CD4 | CD8 | CD25 | CD44 | E2-2 | E2A | E12 | E47 | EBF | Egr1 |HEB | Id1–4 | MEK1 | MEK2 | Pax5 | RAG1 | RAG2 | TGF-β

FURTHER INFORMATIONCornelis Murre’s lab: http://www-biology.ucsd.edu/labs/murre/Encyclopedia of Life Sciences: http://www.els.netLymphocyte developmentAccess to this interactive links box is free online.

the function of e- and id proteins in lymphocyte development

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