HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bhandoola, A. Articles by Schwarz, B. Search for Related Content PubMed PubMed Citation Articles by Bhandoola, A. Articles by Schwarz, B.

Early T Lineage Progenitors: New Insights, but Old Questions Remain

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

T cells developing in the adult thymus ultimately derive from self-renewing hemopoietic stem cells (HSCs)² in the bone marrow (BM). An understanding of the developmental steps linking HSCs to T cells is critical for understanding the T cell defects in aging, the process of malignant transformation in T lineage cells, improving T cell reconstitution after immunotherapy or BM transplantation, and devising gene therapy approaches to correct defects of T cell development and function. In this review, we summarize recent insights into T cell origins, focusing chiefly on adult mice.

The thymus is seeded from the BM

T cells develop within the thymus (1). However, progenitors within the thymus can maintain thymocyte production only for short periods (2, 3). Hence, intrathymic or i.v. transfer of thymocytes results in transient thymopoiesis. BM transferred intrathymically also results in transient thymopoiesis. Only BM transferred i.v. results in sustained thymopoiesis (2, 3). These observations indicate that the thymus does not provide a suitable environment for self-renewal. Instead, seeding of the thymus with BM progenitors is required to maintain thymopoiesis throughout adult life (2, 3).

The thymus is only periodically receptive to seeding from the circulation, suggesting limiting numbers of niches whose occupation precludes further colonization until niche vacancy (4). Past estimates agree that the number of thymic seeding cells must be very small (5, 6), with perhaps 100–300 microenvironmental niches occupied by progenitors that are replaced at an average rate of 2–3% per day (7, 8). These findings highlight the difficulties in using direct approaches to identify and characterize thymus-settling progenitors. Instead, characterization of putative upstream BM progenitors and downstream thymic populations has been used to investigate T cell origins.

Immature thymocyte subsets

Early work demonstrated that immature progenitors within the thymus could be identified within the CD4^-CD8^- double-negative (DN) subset (9, 10). Expression of CD44 and CD25 was used to fractionate the DN population into further subsets that were proposed to constitute a developmental lineage for T cells (11, 12, 13). The most immature progenitors reside within the DN1 CD44⁺CD25^- subset (11, 14), and possess multilineage potential (15). DN2 (CD44⁺CD25⁺) thymocytes lack B lineage potential (15) but are not fully committed to the T lineage, because they remain capable of dendritic cell development (16). Final commitment to the T lineage only occurs at the DN3 (CD44^-CD25⁺) stage, concomitant with extensive rearrangement of TCR , , and genes (17, 18). Productive rearrangement of a TCR chain is necessary for differentiation of DN3 cells into CD4⁺CD8⁺ double-positive (DP) thymocytes (19), which constitute the vast majority of thymocytes. These DP cells initiate rearrangement of the TCR locus (19), followed by TCR-dependent selection (20, 21).

The DN1 population, which contains the most immature T lineage progenitors, is heterogeneous (15). A subset of this population, representing 0.05% of thymocytes (15), expresses high levels of c-Kit (22, 23) and low levels of CD4 (CD4^low) (24), which may be due to passive acquisition (25). These progenitors possess short-term T, B, NKT, as well as NK and dendritic cell potential upon adoptive transfer into irradiated recipients (23, 26, 27, 28). A small degree of myeloid potential was also noted (23, 26). In line with their immature status, they were shown to lack TCR gene rearrangements (17, 29), although a low frequency of D1-J1 rearrangements has been subsequently detected (30).

Further characterization of early T lineage progenitors (ETPs)

Recent work has re-examined the identity and origin of ETPs in adult B6 mice (31). Using an extensive lineage marker (Lin) gate (that lacked anti-CD4) (Table I) to remove differentiated cells, the thymic Lin^-CD44⁺CD25^- population was shown to correspond to a minute 0.01% population. The majority of these Lin^-CD44⁺CD25^- cells were c-Kit^high, stem cell Ag-1 (Sca-1)^high, and IL-7R^neg/low, and were efficient T lineage progenitors. Other subpopulations of the Lin^-CD44⁺CD25^- population lacked T progenitor activity (31). In this review, Lin^-CD44⁺CD25^-c-Kit^high thymocytes are referred to as ETPs after past work (15). As CD44 and c-Kit can be concordantly regulated (32), staining for CD44 is not necessary for identification of ETPs (Table I).

In young adult B6 mice, ETPs represent slightly less than 0.01% of unfractionated thymocytes (1 per 15,000–20,000 thymocytes), and undergo 20,000- to 50,000-fold peak expansion upon intrathymic injection, with the peak occurring 3 wk after transfer (31). In addition to sufficient proliferative ability to generate the number of DP cells that is present in the mouse thymus, the ETP population possesses all lineage potentials known to reside within the DN1 compartment (Ref.31 ; our unpublished data). However, ETPs are too numerous to be the earliest thymus-settling progenitors, given past estimates of the very low number of progenitors that seeds thymus from blood (8). It instead seems likely that the majority of ETPs arise by expansion of small numbers of thymus-settling cells.

BM progenitors for ETPs

The lymphoid restriction and lack of self-renewal ability of early progenitors within the thymus has suggested that they may derive from similar lymphoid-restricted and nonrenewing progenitors within the BM. The identification of the lymphoid-restricted common lymphoid progenitor (CLP) in BM supported this view (35). Identification of CLPs relied on the demonstrated importance of IL-7 in early B and T cell development (35, 38, 39). CLPs were originally identified as Lin^-, IL-7R⁺, c-Kit^low, and Sca-1^low (Table I). CLPs have also been identified using an alternative protocol in which c-Kit is replaced with AA4.1 (40), a mAb that recognizes a protein homologous to C1qR, because CLPs are AA4⁺. However defined, CLPs can be seen to differ by multiple phenotypic criteria from BM LSKs (31) (Table I). CLPs have been suggested to represent a common progenitor for T and B lineages (35) (Fig. 1A). However, CLPs have never been shown to seed the normal thymus, and lymphoid-restricted progenitors with the full panoply of surface markers that define CLPs cannot be detected in normal adult thymus (13, 31, 35). In addition to CLPs, the BM contains other progenitors that will efficiently make T cells in the thymic environment. Most relevant is the BM LSK population, which is upstream of CLPs and contains both Flt3^- self-renewing HSCs, as well as multipotent nonrenewing LSKflt3⁺ progenitors (33, 37) (Table I; Fig. 1).

View larger version (35K): [in this window] [in a new window]   FIGURE 1. Past (A) and revised (B) models of early steps in lymphoid differentiation in BM (beige) and thymus (blue). A, Lymphoid-restricted CLPs arise from self-renewing and multipotent HSCs via a nonrenewing but multipotent LSKflt3+ intermediate. CLPs were previously suggested to represent a common progenitor of T and B lineages. B, The LSKflt3+ population is heterogeneous. A subset of the LSKflt3+ population termed ELP is lymphoid specified, as evidenced by expression of RAG, whereas other LSKflt3+ progenitors are RAG-. ELPs are proposed to give rise to lymphoid-restricted CLPs that in turn give rise to B cells in the BM. ETPs and therefore T cells do not arise from CLPs, but instead arise from progenitor populations upstream of CLPs. These upstream BM progenitors include ELPs, but may also include some HSCs as well as RAG- LSKflt3+ progenitors (designated by the lighter shading around these progenitors). Hence, the split between T and B lineages occurs earlier than had been previously appreciated.

At first glance, ETPs and CLPs appear functionally similar in that they are both lymphoid-restricted nonrenewing progenitors (31, 35, 40). However, unlike CLPs, ETPs possess a weak myeloid differentiation potential (31). In addition, ETPs produce more DP thymocytes for longer periods of time when directly injected into the thymus of sublethally irradiated recipients (31). Conversely, ETPs are inefficient at making B lineage cells compared with CLPs (31). Only small numbers of CD19⁺ B lineage cells appear upon i.v. transfer of ETPs, after protracted periods.

ETPs are not downstream of CLPs

A functional comparison of CLPs and ETPs is difficult to reconcile with a progenitor-successor relationship linking CLPs and ETPs. Instead, a picture emerges of parallel processes of lymphoid differentiation, one in the thymus that results in loss of B lineage potential, and the other in the BM that results in loss of T lineage potential. Differentiation in both sites is linked to loss of myeloid potential, perhaps by down-regulation of necessary cytokine receptors for myeloid development (30, 41).

The phenotypic and functional comparison of ETPs and CLPs suggests that ETPs are more proximal than CLPs to BM LSK progenitors. However, the inefficiency of ETPs in generating B cells suggests that only a small fraction of ETPs possess B lineage potential. Consistently, the limiting number of ETPs necessary to detect B lineage progeny in stromal cell cultures was estimated at 150 (30), whereas the limiting number of CLPs was estimated at 10 (41). The low frequency of B lineage progenitors within the ETP compartment could have two explanations: 1) a small number of thymus-settling progenitors with multilineage potential generates a relatively large pool of progeny that loses B lineage potential; or 2) the majority of thymus-settling cells lose B lineage potential before thymic seeding.

If ETPs and CLPs are not obligatorily linked by a progenitor-successor relationship but instead arise in parallel from LSK progenitors in BM, the requirements for their differentiation may be distinct. Adult Ikaros^-/- mice make T cells but no B cells (42). An examination of early progenitors in Ikaros^-/- mice revealed that they possess ETPs but lack CLPs (31). These findings indicate ETPs develop via a CLP-independent pathway.

It has recently been suggested that B220⁺CD19^-pre-TCR gene (pT)⁺ progeny of CLPs, termed CLP-2s, may seed thymus (43, 44). Cells with a CLP-2 phenotype can be identified in the thymic DN1 compartment of pT reporter mice, but appear considerably less efficient than ETPs in their T lineage potential (44). Furthermore, Ikaros^-/- mice are devoid of B220⁺ cells in BM and spleen (42), but early steps of thymopoiesis in adult Ikaros^-/- mice appear largely intact (31). Hence, it appears unlikely that ETPs are progeny of CLP-2s.

One implication of these findings is that the detection of a lineage potential in experimental assays does not necessarily mean that a progenitor gives rise to cells of that lineage physiologically. It remains to be determined whether T cells can physiologically derive from CLPs, and in which circumstances.

A common progenitor population for T and B cells

As ETPs and CLPs are not linked by a progenitor-successor relationship, the question arises as to the identity of the common progenitor of T and B cells. ETPs are similar in surface phenotype to the BM LSK compartment, which includes HSCs (45, 46) as well as multipotent but nonrenewing progenitors that can be distinguished from HSCs by their expression of Flt3 and CD27, and in Thy1.1-expressing strains only as being Thy1.1^- (33, 37, 45, 47). In this review, the multipotent nonrenewing LSK population is designated LSKflt3⁺ (33). CLPs are now known to arise from the LSKflt3⁺ population, via a differentiation process that requires Flt3 ligand (Flt3L) (33, 48). LSKflt3⁺ progenitors are therefore intermediates between HSCs and CLPs (Fig. 1).

The LSKflt3⁺ population in BM is itself heterogeneous. This was discovered through the analysis of BM progenitors in mice which had green fluorescent protein knocked into the lymphoid-specific gene recombinase-activating gene (RAG)-1 (34). Hemopoietic progenitors that expressed RAG and were green fluorescent protein-positive in these mice were shown to be of two types: 1) an LSK progenitor that is IL-7R^- and Flt3⁺ (and therefore LSKflt3⁺), termed the early lymphoid progenitor (ELP); and 2) a more mature c-Kit^lowSca-1^low cell in which a large fraction express IL-7R and are probably CLPs (34). ELPs possess efficient lymphoid potential but inefficient myeloid potential as compared with RAG^- LSK cells (34). Sca-1^lowc-Kit^lowRAG⁺ progenitors possess only lymphoid potential (34).

A fraction of ELPs possesses D-J IgH rearrangements (34), indicating that RAG is functional at this early stage. ETPs and CLPs also possess D-J IgH rearrangements (31), consistent with an origin from ELPs. This provides one explanation for the presence of D-J IgH rearrangements in mature T cells (49). ELPs are therefore a plausible progenitor population for both ETPs and CLPs (Fig. 1B).

Lymphoid specification in ELPs

The expression of RAG by ELPs indicates that lymphoid specification initiates earlier than previously appreciated (34). Expression of RAG is currently the earliest marker for hemopoietic progenitors undergoing lymphoid specification, because it precedes the expression of IL-7R (34).

Lymphopoiesis in RAG-deficient mice arrests in T lineage cells at the pre-TCR checkpoint, and in B lineage cells at the pre-BCR checkpoint (13). Early expression of RAG in the BM is therefore unlikely to be required for lymphoid development. Furthermore, when HSCs are directly injected into the thymus, T cell development ensues (7, 33), indicating that early lymphoid specification in the BM is not necessary for development of T cells in the thymus. At this time, it remains mysterious as to why RAG is expressed so early in hemopoietic development. Early expression of RAG may reflect coordinate regulation of RAG with other genes important for early steps of lymphoid development in the BM. Further study of the signals that turn on RAG, as well as identification of coordinately regulated genes, may provide an understanding of this earliest known step in lymphoid specification.

Regulation of RAG is complex, and different locus control elements are responsible for RAG expression in B vs T lineage cells (50, 51). Whether different control elements are responsible for RAG expression in different progenitor populations such as CLPs, ETPs, and ELPs or ELP subsets has not been determined. In this regard, ELPs possess robust T and B lineage potential at the population level (34), but single-cell assays have not yet been performed. Such assays have been performed in neonatal fetal liver (52). The surprising result is that progenitors with only T/B potential cannot be identified. Instead, T lineage-committed cells appear to arise from multipotent progenitors via an intermediate with T and myeloid lineage potential (52). These results suggest ELPs may turn out to be a heterogeneous progenitor pool, with separate progenitors possessing T or B lineage potential. Consistent with such a perspective, recent work (in Thy1.1 mice only) has identified a Thy1.1^- BM LSK population that possesses efficient T progenitor activity but inefficient B and myeloid progenitor activity (53).

From BM to blood

Rescue of lethally irradiated mice with blood leukocytes was demonstrated over 40 years ago, indicating that HSCs must circulate in blood (54). More recent work has confirmed that parabiosed mice (in which the circulation of two mice is anastomosed) exchange HSCs (55). Therefore, it appears that HSCs normally circulate in search of vacant stem cell and perhaps thymic niches (56). Progenitors in blood are present at a frequency too low to allow direct identification, but CFU-cell are present in blood at a frequency of 1:10⁵ WBCs, and day 12 CFU-spleen in blood have been estimated at a frequency of 0.3:10⁵ WBCs (57). Because HSCs are also present in blood, the identity and lineage restriction of additional progenitors is difficult to address using in vivo experiments, because the huge proliferative capacity of HSCs means that their progeny dominate in such experiments (7).

From blood to thymus

Given that HSCs are likely to circulate in blood (54, 55), one must ask whether such HSCs also seed the adult thymus. Intravenous transfer of ETPs or other thymic progenitor populations does not result in sustained multilineage reconstitution in recipient mice (3, 31), suggesting that self-renewing HSCs at most constitute a very small fraction of ETPs. In recent work, irradiated mice were inoculated i.v. with lineage-depleted BM, and thymus-settling progenitors were found to be largely restricted to the lymphoid lineage (58). However, it remains possible that thymic colonization is effected by a small number of HSCs and/or multipotent progenitors, if such colonization is accompanied by a rapid loss of self-renewal capability and nonlymphoid lineage potentials (15). More work is needed to determine which progenitors physiologically seed the adult thymus.

CD25 and c-Kit expression have been used to characterize progenitor migration from the blood into the thymus (59). In this work, c-Kit⁺CD25^- cells were shown to enter in a narrow zone in the perimedullary cortex, and migrate via the cortex toward the subcapsular area (59). There are substantial opportunities for interaction of T lineage progenitors with thymic stromal cells (59, 60) that likely play a key role in guiding early steps of intrathymic T lineage specification.

Environmental signals

Cytokines as well as Notch signals are critically required at the earliest stages of T lineage development. Cytokines are thought to function by supporting survival and proliferation (38, 61, 62, 63), and a role in cellular trafficking has also been suggested (60), whereas Notch is thought to play a key role in commitment to the T cell lineage (64). However, the stage at which development arrests in the absence of cytokines or Notch signals, and whether development arrests at a single defined stage, are less well characterized than for downstream RAG-dependent checkpoints (20).

Cytokines

Stem cell factor and IL-7 are cytokines known to be important in early T cell development (63, 65), and the thymus in c-Kit^w/w_c^-/- neonatal mice is essentially alymphoid (63). A viable c-Kit^w/w variant (Vickid) that survives to adulthood and displays severe blocks in very early T cell development has been reported (66). IL-7 or IL-7R knockouts show a 100-fold reduction in thymic cellularity (38, 65), but all stages of development of lineage cells are present, whereas cells fail to develop. IL-7 plays an important role in differentiation of DN2 thymocytes to T lineage-committed DN3 cells (38). Whether IL-7 plays an additional role in adult thymopoiesis before the DN2 stage remains to be determined. No alterations in thymopoiesis have been reported in Flt3^-/- mice (67), but a modest reduction in DN2 but not DN3 or DP thymocytes has been reported in Flt3L^-/- mice (48). Hence, Flt3 and Flt3L may play a role at early stages of intrathymic T lineage development, although such a role may be obscured in Flt3^-/- and Flt3L^-/- mice by compensatory mechanisms.

Notch

Four Notch receptors (Notch 1–4), and five Notch transmembrane ligands (Jagged1, Jagged2, and Delta-like 1, 3, and 4) have been described in mice (64). Inducible inactivation of Notch1 results in an early block in intrathymic T lineage differentiation at the DN1 stage, and accumulation of increased numbers of B lineage cells in the thymus (68). Conversely, overexpression of constitutively active Notch1 in hemopoietic progenitors results in development of T lineage cells to the DP stage in the BM, whereas B lineage development is abrogated at an early stage (69). In these reports, myeloid development in BM appears unaffected (68, 69). Additional work has verified and extended these findings (70, 71).

Extrathymic T lineage development in the gut is known to be Notch1 dependent (72). T lineage-committed progenitors have been demonstrated in fetal liver (73) as well as spleen of irradiated mice given BM i.v. (74), but it is unknown whether commitment to the T lineage in these circumstances is Notch dependent. Compellingly, when BM stromal cells expressing a retrovirally encoded Notch ligand Delta-like 1 are cultured with multipotent progenitors from fetal liver, T lineage cells are generated (Ref.75); also see Ref.76), whereas the parental cell line supports B lineage development only.

Known target genes for Notch signaling in T lineage cells include hairy/enhancer of split (Hes)1, Hes5, Deltex1, and Notch1 itself (64, 77). pT is a plausible T lineage-specific target of Notch (78). Both Hes1 and Hes5 inhibit B lineage development from multipotent progenitors when retrovirally overexpressed in hemopoietic progenitors (79). Hes1-deficient mice have a partial defect in early T lineage development (80). In fetal mice, early progenitors have been identified both adjacent to as well as within the developing thymus. Examination of these progenitor populations reveals expression of known Notch target genes in progenitors within the thymus, but little expression in progenitors that have not yet entered the fetal thymus (81).

Taken together, these data suggest that one distinguishing (but not unique) feature of the thymic environment may be the ability to send strong Notch signals into colonizing progenitors, possibly due to expression of key Notch ligands on thymic stromal cells. All other features of the thymic and BM environments appear permissible for both T and B lineage development.

The T vs B decision

The Notch data have been interpreted as strong genetic evidence for a T/B lineage commitment decision that is controlled in a bipotent progenitor by the presence of signals downstream of Notch1 (68, 69). The simplest model based on these data is that progenitors with T and B potential colonize the thymus and subsequently receive Notch1 signals, resulting in loss of B lineage potential. The same progenitors in the BM that avoid Notch1 signals commit to the B lineage. This is an attractive model but may be an oversimplification. The known data are compatible with the possibility that a range of progenitors colonizes the thymus, including multipotent progenitors as well as lineage-restricted progenitors such as ELPs. T lineage progression in all of these progenitors would depend on Notch signaling. Loss of nonlymphoid potentials in multipotent progenitors that colonize the thymus may occur via Notch-dependent mechanisms that operate within the thymic context, by Notch-independent mechanisms, or by both.

T cell origins

Recent work makes it appear unlikely that T cells derive from CLPs as previously proposed (Fig. 1A). ETPs may instead derive from the BM LSK compartment, which is upstream of CLPs (Fig. 1B). The ELP subset of BM LSKs is undergoing a process of lymphoid specification, as evidenced by RAG expression and D-J IgH rearrangements. D-J IgH rearrangements are present in ETPs and CLPs, suggesting that ELPs represent a common progenitor population for T and B cells.

Of the progenitors in the BM LSK compartment, HSCs also circulate in blood. RAG⁺ ELPs and RAG^- LSKflt3⁺ progenitors may also circulate in blood. Small numbers of these circulating progenitors likely seed the thymus, where they undergo cytokine-mediated expansion overlapping with Notch-mediated progression down the T lineage pathway. Therefore, it is suggested that ETPs derive from a heterogeneous pool of progenitors. The earliest steps of lymphoid specification in BM are beginning to be explored, and the mechanisms by which Notch plays such a critical role in T lineage development are beginning to be unraveled. The small number of thymus-colonizing progenitors makes it likely that their identification in normal mice will elude direct approaches in the near future. Where and how early progenitors integrate signals from their environment, resulting in loss of alternative lineage potentials and progression down the T lineage pathway, all remain to be elucidated. The challenge is to develop techniques that allow more sophisticated and quantitative inquiry into the earliest steps of T lineage specification and subsequent commitment.

	Acknowledgments

 
We thank Drs. Howard T. Petrie, Michael P. Cancro, Ivan Maillard, and Dina Fonseca for critical comments.

	Footnotes

 
¹ Address correspondence and reprint requests to Dr. Avinash Bhandoola, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160. E-mail address: bhandooa{at}mail.med.upenn.edu

² Abbreviations used in this paper: HSC, hemopoietic stem cell; BM, bone marrow; DN, CD4^-CD8^- double negative; DP, CD4⁺CD8⁺ double positive; ETP, early T lineage progenitor; CLP, common lymphoid progenitor; ELP, early lymphoid progenitor; Lin, lineage marker; Sca-1, stem cell Ag-1; LSK, Lin^-Sca-1^highc-Kit^high; RAG, recombinase-activating gene; Flt3, fms-like tyrosine kinase 3; Flt3L, Flt3 ligand; pT, pre-TCR gene; Hes, hairy/enhancer of split.

Received for publication August 18, 2003. Accepted for publication September 2, 2003.

	References

Top References

 

1. Miller, J. F., D. Osoba. 1967. Current concepts of the immunological function of the thymus. Physiol. Rev. 47:437.[Free Full Text]
2. Goldschneider, I., K. L. Komschlies, D. L. Greiner. 1986. Studies of thymocytopoiesis in rats and mice. I. Kinetics of appearance of thymocytes using a direct intrathymic adoptive transfer assay for thymocyte precursors. J. Exp. Med. 163:1.[Abstract/Free Full Text]
3. Scollay, R., J. Smith, V. Stauffer. 1986. Dynamics of early T cells: prothymocyte migration and proliferation in the adult mouse thymus. Immunol. Rev. 91:129.[Medline]
4. Foss, D. L., E. Donskoy, I. Goldschneider. 2001. The importation of hematogenous precursors by the thymus is a gated phenomenon in normal adult mice. J. Exp. Med. 193:365.[Abstract/Free Full Text]
5. Wallis, V. J., E. Leuchars, S. Chwalinski, A. J. Davies. 1975. On the sparse seeding of bone marrow and thymus in radiation chimaeras. Transplantation 19:2.[Medline]
6. Kadish, J. L., R. S. Basch. 1976. Hematopoietic thymocyte precursors. I. Assay and kinetics of the appearance of progeny. J. Exp. Med. 143:1082.[Abstract/Free Full Text]
7. Spangrude, G. J., R. Scollay. 1990. Differentiation of hematopoietic stem cells in irradiated mouse thymic lobes: kinetics and phenotype of progeny. J. Immunol. 145:3661.[Abstract]
8. Donskoy, E., I. Goldschneider. 1992. Thymocytopoiesis is maintained by blood-borne precursors throughout postnatal life: a study in parabiotic mice. J. Immunol. 148:1604.[Abstract]
9. Fowlkes, B. J., L. Edison, B. J. Mathieson, T. M. Chused. 1985. Early T lymphocytes: differentiation in vivo of adult intrathymic precursor cells. J. Exp. Med. 162:802.[Abstract/Free Full Text]
10. Ceredig, R., R. P. Sekaly, H. R. MacDonald. 1983. Differentiation in vitro of Lyt 2⁺ thymocytes from embryonic Lyt 2^- precursors. Nature 303:248.[Medline]
11. Pearse, M., L. Wu, M. Egerton, A. Wilson, K. Shortman, R. Scollay. 1989. A murine early thymocyte developmental sequence is marked by transient expression of the interleukin 2 receptor. Proc. Natl. Acad. Sci. USA 86:1614.[Abstract/Free Full Text]
12. Godfrey, D. I., J. Kennedy, T. Suda, A. Zlotnik. 1993. A developmental pathway involving four phenotypically and functionally distinct subsets of CD3^-CD4^-CD8^- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J. Immunol. 150:4244.[Abstract]
13. Ceredig, R., T. Rolink. 2002. A positive look at double-negative thymocytes. Nat. Rev. Immunol. 2:888.[Medline]
14. Shimonkevitz, R. P., L. A. Husmann, M. J. Bevan, I. N. Crispe. 1987. Transient expression of IL-2 receptor precedes the differentiation of immature thymocytes. Nature 329:157.[Medline]
15. Shortman, K., L. Wu. 1996. Early T lymphocyte progenitors. Annu. Rev. Immunol. 14:29.[Medline]
16. Wu, L., C. L. Li, K. Shortman. 1996. Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny. J. Exp. Med. 184:903.[Abstract/Free Full Text]
17. Ismaili, J., M. Antica, L. Wu. 1996. CD4 and CD8 expression and T cell antigen receptor gene rearrangement in early intrathymic precursor cells. Eur. J. Immunol. 26:731.[Medline]
18. Capone, M., R. D. Hockett, Jr., A. Zlotnik. 1998. Kinetics of T cell receptor , , and rearrangements during adult thymic development: T cell receptor rearrangements are present in CD44⁺CD25⁺ pro-T thymocytes. Proc. Natl. Acad. Sci. USA 95:12522.[Abstract/Free Full Text]
19. von Boehmer, H., I. Aifantis, J. Feinberg, O. Lechner, C. Saint-Ruf, U. Walter, J. Buer, O. Azogui. 1999. Pleiotropic changes controlled by the pre-T-cell receptor. Curr. Opin. Immunol. 11:135.[Medline]
20. Robey, E., B. J. Fowlkes. 1994. Selective events in T cell development. Annu. Rev. Immunol. 12:675.[Medline]
21. Singer, A.. 2002. New perspectives on a developmental dilemma: the kinetic signaling model and the importance of signal duration for the CD4/CD8 lineage decision. Curr. Opin. Immunol. 14:207.[Medline]
22. Godfrey, D. I., A. Zlotnik, T. Suda. 1992. Phenotypic and functional characterization of c-kit expression during intrathymic T cell development. J. Immunol. 149:2281.[Abstract]
23. Matsuzaki, Y., J. Gyotoku, M. Ogawa, S. Nishikawa, Y. Katsura, G. Gachelin, H. Nakauchi. 1993. Characterization of c-kit positive intrathymic stem cells that are restricted to lymphoid differentiation. J. Exp. Med. 178:1283.[Abstract/Free Full Text]
24. Wu, L., R. Scollay, M. Egerton, M. Pearse, G. J. Spangrude, K. Shortman. 1991. CD4 expressed on earliest T-lineage precursor cells in the adult murine thymus. Nature 349:71.[Medline]
25. Michie, A. M., J. R. Carlyle, J. C. Zuniga-Pflucker. 1998. Early intrathymic precursor cells acquire a CD4^low phenotype. J. Immunol. 160:1735.[Abstract/Free Full Text]
26. Wu, L., M. Antica, G. R. Johnson, R. Scollay, K. Shortman. 1991. Developmental potential of the earliest precursor cells from the adult mouse thymus. J. Exp. Med. 174:1617.[Abstract/Free Full Text]
27. Ardavin, C., L. Wu, C. L. Li, K. Shortman. 1993. Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population. Nature 362:761.[Medline]
28. Moore, T. A., A. Zlotnik. 1995. T-cell lineage commitment and cytokine responses of thymic progenitors. Blood 86:1850.[Abstract/Free Full Text]
29. Petrie, H. T., F. Livak, D. Burtrum, S. Mazel. 1995. T cell receptor gene recombination patterns and mechanisms: cell death, rescue, and T cell production. J. Exp. Med. 182:121.[Abstract/Free Full Text]
30. King, A. G., M. Kondo, D. C. Scherer, I. L. Weissman. 2002. Lineage infidelity in myeloid cells with TCR gene rearrangement: a latent developmental potential of proT cells revealed by ectopic cytokine receptor signaling. Proc. Natl. Acad. Sci. USA 99:4508.[Abstract/Free Full Text]
31. Allman, D., A. Sambandam, S. Kim, J. P. Miller, A. Pagan, D. Well, A. Meraz, A. Bhandoola. 2003. Thymopoiesis independent of common lymphoid progenitors. Nat. Immunol. 4:168.[Medline]
32. Diamond, R. A., S. B. Ward, K. Owada-Makabe, H. Wang, E. V. Rothenberg. 1997. Different developmental arrest points in RAG-2^-/- and SCID thymocytes on two genetic backgrounds: developmental choices and cell death mechanisms before TCR gene rearrangement. J. Immunol. 158:4052.[Abstract]
33. Adolfsson, J., O. J. Borge, D. Bryder, K. Theilgaard-Monch, I. Astrand-Grundstrom, E. Sitnicka, Y. Sasaki, S. E. Jacobsen. 2001. Upregulation of Flt3 expression within the bone marrow Lin^-Sca1⁺c-kit⁺ stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15:659.[Medline]
34. Igarashi, H., S. Gregory, T. Yokota, N. Sakaguchi, P. Kincade. 2002. Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. Immunity 17:117.[Medline]
35. Kondo, M., I. L. Weissman, K. Akashi. 1997. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91:661.[Medline]
36. D’Amico, A., L. Wu. 2003. The early progenitors of mouse dendritic cells and plasmacytoid predendritic cells are within the bone marrow hemopoietic precursors expressing Flt3. J. Exp. Med. 198:293.[Abstract/Free Full Text]
37. Christensen, J. L., I. L. Weissman. 2001. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc. Natl. Acad. Sci. USA 98:14541.[Abstract/Free Full Text]
38. Peschon, J. J., P. J. Morrissey, K. H. Grabstein, F. J. Ramsdell, E. Maraskovsky, B. C. Gliniak, L. S. Park, S. F. Ziegler, D. E. Williams, C. B. Ware, et al 1994. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180:1955.[Abstract/Free Full Text]
39. von Freeden-Jeffry, U., N. Solvason, M. Howard, R. Murray. 1997. The earliest T lineage-committed cells depend on IL-7 for Bcl-2 expression and normal cell cycle progression. Immunity 7:147.[Medline]
40. Izon, D., K. Rudd, W. DeMuth, W. S. Pear, C. Clendenin, R. C. Lindsley, D. Allman. 2001. A common pathway for dendritic cell and early B cell development. J. Immunol. 167:1387.[Abstract/Free Full Text]
41. Kondo, M., D. C. Scherer, T. Miyamoto, A. G. King, K. Akashi, K. Sugamura, I. L. Weissman. 2000. Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines. Nature 407:383.[Medline]
42. Wang, J. H., A. Nichogiannopoulou, L. Wu, L. Sun, A. H. Sharpe, M. Bigby, K. Georgopoulos. 1996. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5:537.[Medline]
43. Gounari, F., I. Aifantis, C. Martin, H. J. Fehling, S. Hoeflinger, P. Leder, H. von Boehmer, B. Reizis. 2002. Tracing lymphopoiesis with the aid of a pT-controlled reporter gene. Nat. Immunol. 3:489.[Medline]
44. Martin, C. H., I. Aifantis, M. L. Scimone, U. H. Von Andrian, B. Reizis, H. Von Boehmer, F. Gounari. 2003. Efficient thymic immigration of B220⁺ lymphoid-restricted bone marrow cells with T precursor potential. Nat. Immunol. 4:866.[Medline]
45. Spangrude, G. J., S. Heimfeld, I. L. Weissman. 1988. Purification and characterization of mouse hematopoietic stem cells. Science 241:58.[Abstract/Free Full Text]
46. Ikuta, K., I. L. Weissman. 1992. Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proc. Natl. Acad. Sci. USA 89:1502.[Abstract/Free Full Text]
47. Wiesmann, A., R. L. Phillips, M. Mojica, L. J. Pierce, A. E. Searles, G. J. Spangrude, I. Lemischka. 2000. Expression of CD27 on murine hematopoietic stem and progenitor cells. Immunity 12:193.[Medline]
48. Sitnicka, E., D. Bryder, K. Theilgaard-Monch, N. Buza-Vidas, J. Adolfsson, S. E. Jacobsen. 2002. Key role of flt3 ligand in regulation of the common lymphoid progenitor but not in maintenance of the hematopoietic stem cell pool. Immunity 17:463.[Medline]
49. Born, W., J. White, J. Kappler, P. Marrack. 1988. Rearrangement of IgH genes in normal thymocyte development. J. Immunol. 140:3228.[Abstract]
50. Yu, W., Z. Misulovin, H. Suh, R. R. Hardy, M. Jankovic, N. Yannoutsos, M. C. Nussenzweig. 1999. Coordinate regulation of RAG1 and RAG2 by cell type-specific DNA elements 5' of RAG2. Science 285:1080.[Abstract/Free Full Text]
51. Hsu, L. Y., J. Lauring, H. E. Liang, S. Greenbaum, D. Cado, Y. Zhuang, M. S. Schlissel. 2003. A conserved transcriptional enhancer regulates RAG gene expression in developing B cells. Immunity 19:105.[Medline]
52. Katsura, Y.. 2002. Redefinition of lymphoid progenitors. Nat. Rev. Immunol. 2:127.[Medline]
53. Perry, S. S., L. J. Pierce, W. B. Slayton, G. J. Spangrude. 2003. Characterization of thymic progenitors in adult mouse bone marrow. J. Immunol. 170:1877.[Abstract/Free Full Text]
54. Goodman, J. W., G. S. Hodgson. 1962. Evidence for stem cells in the peripheral blood of mice. Blood 19:702.[Abstract/Free Full Text]
55. Wright, D. E., A. J. Wagers, A. P. Gulati, F. L. Johnson, I. L. Weissman. 2001. Physiological migration of hematopoietic stem and progenitor cells. Science 294:1933.[Abstract/Free Full Text]
56. Weissman, I. L.. 2002. The road ended up at stem cells. Immunol. Rev. 185:159.[Medline]
57. Yamamoto, Y., R. Yasumizu, Y. Amou, N. Watanabe, N. Nishio, J. Toki, S. Fukuhara, S. Ikehara. 1996. Characterization of peripheral blood stem cells in mice. Blood 88:445.[Abstract/Free Full Text]
58. Mori, S., K. Shortman, L. Wu. 2001. Characterization of thymus-seeding precursor cells from mouse bone marrow. Blood 98:696.[Abstract/Free Full Text]
59. Lind, E. F., S. E. Prockop, H. E. Porritt, H. T. Petrie. 2001. Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J. Exp. Med. 194:127.[Abstract/Free Full Text]
60. Prockop, S., H. T. Petrie. 2000. Cell migration and the anatomic control of thymocyte precursor differentiation. Semin. Immunol. 12:435.[Medline]
61. Kim, K., C. K. Lee, T. J. Sayers, K. Muegge, S. K. Durum. 1998. The trophic action of IL-7 on pro-T cells: inhibition of apoptosis of pro-T1, -T2, and -T3 cells correlates with Bcl-2 and Bax levels and is independent of Fas and p53 pathways. J. Immunol. 160:5735.[Abstract/Free Full Text]
62. Rodewald, H. R., K. Kretzschmar, W. Swat, S. Takeda. 1995. Intrathymically expressed c-kit ligand (stem cell factor) is a major factor driving expansion of very immature thymocytes in vivo. Immunity 3:313.[Medline]
63. Rodewald, H. R., M. Ogawa, C. Haller, C. Waskow, J. P. DiSanto. 1997. Pro-thymocyte expansion by c-kit and the common cytokine receptor gamma chain is essential for repertoire formation. Immunity 6:265.[Medline]
64. Allman, D., J. A. Punt, D. J. Izon, J. C. Aster, W. S. Pear. 2002. An invitation to T and more: Notch signaling in lymphopoiesis. Cell 109:(Suppl.):S1.
65. von Freeden-Jeffry, U., P. Vieira, L. A. Lucian, T. McNeil, S. E. Burdach, R. Murray. 1995. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181:1519.[Abstract/Free Full Text]
66. Waskow, C., S. Paul, C. Haller, M. Gassmann, H. Rodewald. 2002. Viable c-Kit^W/W mutants reveal pivotal role for c-kit in the maintenance of lymphopoiesis. Immunity 17:277.[Medline]
67. Mackarehtschian, K., J. D. Hardin, K. A. Moore, S. Boast, S. P. Goff, I. R. Lemischka. 1995. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 3:147.[Medline]
68. Radtke, F., A. Wilson, G. Stark, M. Bauer, J. van Meerwijk, H. R. MacDonald, M. Aguet. 1999. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10:547.[Medline]
69. Pui, J. C., D. Allman, L. Xu, S. DeRocco, F. G. Karnell, S. Bakkour, J. Y. Lee, T. Kadesch, R. R. Hardy, J. C. Aster, W. S. Pear. 1999. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 11:299.[Medline]
70. Koch, U., T. A. Lacombe, D. Holland, J. L. Bowman, B. L. Cohen, S. E. Egan, C. J. Guidos. 2001. Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1. Immunity 15:225.[Medline]
71. Han, H., K. Tanigaki, N. Yamamoto, K. Kuroda, M. Yoshimoto, T. Nakahata, K. Ikuta, T. Honjo. 2002. Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. Int. Immunol. 14:637.[Abstract/Free Full Text]
72. Wilson, A., I. Ferrero, H. R. MacDonald, F. Radtke. 2000. Cutting edge: an essential role for Notch-1 in the development of both thymus-independent and -dependent T cells in the gut. J. Immunol. 165:5397.[Abstract/Free Full Text]
73. Kawamoto, H., T. Ikawa, K. Ohmura, S. Fujimoto, Y. Katsura. 2000. T cell progenitors emerge earlier than B cell progenitors in the murine fetal liver. Immunity 12:441.[Medline]
74. Lancrin, C., E. Schneider, F. Lambolez, M. L. Arcangeli, C. Garcia-Cordier, B. Rocha, S. Ezine. 2002. Major T cell progenitor activity in bone marrow-derived spleen colonies. J. Exp. Med. 195:919.[Abstract/Free Full Text]
75. Schmitt, T. M., J. C. Zuniga-Pflucker. 2002. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 17:749.[Medline]
76. Jaleco, A. C., H. Neves, E. Hooijberg, P. Gameiro, N. Clode, M. Haury, D. Henrique, L. Parreira. 2001. Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J. Exp. Med. 194:991.[Abstract/Free Full Text]
77. Deftos, M. L., E. Huang, E. W. Ojala, K. A. Forbush, M. J. Bevan. 2000. Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. Immunity 13:73.[Medline]
78. Reizis, B., P. Leder. 2002. Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway. Genes Dev. 16:295.[Abstract/Free Full Text]
79. Kawamata, S., C. Du, K. Li, C. Lavau. 2002. Overexpression of the Notch target genes Hes in vivo induces lymphoid and myeloid alterations. Oncogene 21:3855.[Medline]
80. Tomita, K., M. Hattori, E. Nakamura, S. Nakanishi, N. Minato, R. Kageyama. 1999. The bHLH gene Hes1 is essential for expansion of early T cell precursors. Genes Dev. 13:1203.[Abstract/Free Full Text]
81. Harman, B. C., E. J. Jenkinson, G. Anderson. 2003. Microenvironmental regulation of Notch signalling in T cell development. Semin. Immunol. 15:91.[Medline]

This article has been cited by other articles:

				C. T. Jensen, C. Boiers, S. Kharazi, A. Lubking, T. Ryden, M. Sigvardsson, E. Sitnicka, and S. E. W. Jacobsen Permissive roles of hematopoietin and cytokine tyrosine kinase receptors in early T-cell development Blood, February 15, 2008; 111(4): 2083 - 2090. [Abstract] [Full Text] [PDF]

				Q.-L. Hao, A. A. George, J. Zhu, L. Barsky, E. Zielinska, X. Wang, M. Price, S. Ge, and G. M. Crooks Human intrathymic lineage commitment is marked by differential CD7 expression: identification of CD7- lympho-myeloid thymic progenitors Blood, February 1, 2008; 111(3): 1318 - 1326. [Abstract] [Full Text] [PDF]

				E. Sitnicka, N. Buza-Vidas, H. Ahlenius, C. M. Cilio, C. Gekas, J. M. Nygren, R. Mansson, M. Cheng, C. T. Jensen, M. Svensson, et al. Critical role of FLT3 ligand in IL-7 receptor independent T lymphopoiesis and regulation of lymphoid-primed multipotent progenitors Blood, October 15, 2007; 110(8): 2955 - 2964. [Abstract] [Full Text] [PDF]

				C. C. Tydell, E.-S. David-Fung, J. E. Moore, L. Rowen, T. Taghon, and E. V. Rothenberg Molecular Dissection of Prethymic Progenitor Entry into the T Lymphocyte Developmental Pathway J. Immunol., July 1, 2007; 179(1): 421 - 438. [Abstract] [Full Text] [PDF]

				L. C. Osborne, S. Dhanji, J. W. Snow, J. J. Priatel, M. C. Ma, M. J. Miners, H.-S. Teh, M. A. Goldsmith, and N. Abraham Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7R{alpha} mutant mice J. Exp. Med., March 19, 2007; 204(3): 619 - 631. [Abstract] [Full Text] [PDF]

				S. Ichimiya and T. Kojima Cellular Networks of Human Thymic Medullary Stromas Coordinated by p53-Related Transcription Factors J. Histochem. Cytochem., November 1, 2006; 54(11): 1277 - 1289. [Abstract] [Full Text] [PDF]

				T. Yahata, S. Yumino, Y. Seng, H. Miyatake, T. Uno, Y. Muguruma, M. Ito, H. Miyoshi, S. Kato, T. Hotta, et al. Clonal analysis of thymus-repopulating cells presents direct evidence for self-renewal division of human hematopoietic stem cells Blood, October 1, 2006; 108(7): 2446 - 2454. [Abstract] [Full Text] [PDF]

				S. S. Perry, R. S. Welner, T. Kouro, P. W. Kincade, and X.-H. Sun Primitive lymphoid progenitors in bone marrow with T lineage reconstituting potential. J. Immunol., September 1, 2006; 177(5): 2880 - 2887. [Abstract] [Full Text] [PDF]

				M. L. Scimone, I. Aifantis, I. Apostolou, H. von Boehmer, and U. H. von Andrian A multistep adhesion cascade for lymphoid progenitor cell homing to the thymus PNAS, May 2, 2006; 103(18): 7006 - 7011. [Abstract] [Full Text] [PDF]

				F. Weerkamp, M. R. M. Baert, M. H. Brugman, W. A. Dik, E. F. E. de Haas, T. P. Visser, C. J. M. de Groot, G. Wagemaker, J. J. M. van Dongen, and F. J. T. Staal Human thymus contains multipotent progenitors with T/B lymphoid, myeloid, and erythroid lineage potential Blood, April 15, 2006; 107(8): 3131 - 3137. [Abstract] [Full Text] [PDF]

				H. Min, E. Montecino-Rodriguez, and K. Dorshkind Effects of Aging on the Common Lymphoid Progenitor to Pro-B Cell Transition J. Immunol., January 15, 2006; 176(2): 1007 - 1012. [Abstract] [Full Text] [PDF]

				M. R. Ryan, R. Shepherd, J. K. Leavey, Y. Gao, F. Grassi, F. J. Schnell, W.-P. Qian, G. J. Kersh, M. N. Weitzmann, and R. Pacifici An IL-7-dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency PNAS, November 15, 2005; 102(46): 16735 - 16740. [Abstract] [Full Text] [PDF]

				J. Huang, K. P. Garrett, R. Pelayo, J. C. Zuniga-Pflucker, H. T. Petrie, and P. W. Kincade Propensity of Adult Lymphoid Progenitors to Progress to DN2/3 Stage Thymocytes with Notch Receptor Ligation J. Immunol., October 15, 2005; 175(8): 4858 - 4865. [Abstract] [Full Text] [PDF]

				O. Adjali, R. R. Vicente, C. Ferrand, C. Jacquet, C. Mongellaz, P. Tiberghien, K. Chebli, V. S. Zimmermann, and N. Taylor Intrathymic administration of hematopoietic progenitor cells enhances T cell reconstitution in ZAP-70 severe combined immunodeficiency PNAS, September 20, 2005; 102(38): 13586 - 13591. [Abstract] [Full Text] [PDF]

				T. S. P. Heng, G. L. Goldberg, D. H. D. Gray, J. S. Sutherland, A. P. Chidgey, and R. L. Boyd Effects of Castration on Thymocyte Development in Two Different Models of Thymic Involution J. Immunol., September 1, 2005; 175(5): 2982 - 2993. [Abstract] [Full Text] [PDF]

				L. M. C. Webb Extrathymic commitment to T-cell lineage Blood, August 1, 2005; 106(3): 770 - 771. [Full Text] [PDF]

				C. Benz and C. C. Bleul A multipotent precursor in the thymus maps to the branching point of the T versus B lineage decision J. Exp. Med., July 5, 2005; 202(1): 21 - 31. [Abstract] [Full Text] [PDF]

				T. J. Fry and C. L. Mackall The Many Faces of IL-7: From Lymphopoiesis to Peripheral T Cell Maintenance J. Immunol., June 1, 2005; 174(11): 6571 - 6576. [Abstract] [Full Text] [PDF]

				S. M. Lehar, J. Dooley, A. G. Farr, and M. J. Bevan Notch ligands Delta1 and Jagged1 transmit distinct signals to T-cell precursors Blood, February 15, 2005; 105(4): 1440 - 1447. [Abstract] [Full Text] [PDF]

				S. Hoflinger, K. Kesavan, M. Fuxa, C. Hutter, B. Heavey, F. Radtke, and M. Busslinger Analysis of Notch1 Function by In Vitro T Cell Differentiation of Pax5 Mutant Lymphoid Progenitors J. Immunol., September 15, 2004; 173(6): 3935 - 3944. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bhandoola, A. Articles by Schwarz, B. Search for Related Content PubMed PubMed Citation Articles by Bhandoola, A. Articles by Schwarz, B.