Critical role for c‐kit (CD117) in T cell lineage commitment and early thymocyte development <i>in vitro</i>

Massa, Steffen; Balc̆iūnaite, Gina; Ceredig, Rhodri; Rolink, Antonius

doi:10.1002/eji.200535760

Cited by 74 publications

(80 citation statements)

References 19 publications

(30 reference statements)

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“…within hours of culture of Pax5 -/-pro-B cells on OP9-DL1 stroma. These findings imply a 'close link' between Notch signaling and upregulation of c-Kit in these progenitors, and this marked increase in cKit expression appears to be one of the earliest responses of T cell progenitors to Notch signaling [6,12].…”

mentioning

confidence: 81%

“…Finally, a third area of interest is the regulation of c-Kit expression during hematopoiesis. As pointed out by Rolink and colleagues in this issue of the European Journal of Immunology [6], and discussed below, expression levels of c-Kit vary considerably in different stages and lineages. Specifically, signals enforcing or re-enforcing c-Kit expression in lymphocyte progenitors were largely unknown.…”

mentioning

confidence: 94%

“…Very few phenotypically identifiable pro-T and pro-B cells can be identified in these mutants, and these putative progenitors lack expression of stagespecific hallmark genes such as Rag1 and Rag2, common for T and B progenitors, and pTa and k5, characteristic for T and B progenitors respectively [5]. Moreover, both CD19 -(uncommitted) and CD19 + (committed) precursor (pre-) B cells (for a definition of pre-B in these experiments, see [5,6]) from adult c-Kit W/W mice are almost completely devoid of clonable B cell progenitors [5].…”

mentioning

confidence: 95%

“…The study by Massa et al [6] provides evidence for an interesting link between c-Kit and Notch. Interactions between Notch and its ligand (e.g.…”

mentioning

confidence: 97%

“…Expression of c-Kit is low on Pax5 -/-pro-B cells, a property these cells share with 'normal' pro-B cells and various common lymphocyte progenitor phenotypes (see below). The groups of Rolink [6] and Busslinger [12] both noticed an upregulation of c-Kit expression within 1 to 3 days after culture of Pax5 -/-pro-B cells in the presence of stromal cells (OP9-DL1) expressing one of the Notch ligands, Delta-like-1, but not in the presence of stromal cells (OP-9) lacking Delta-like-1. The OP9-DL1 culture system efficiently supports T cell development from uncommitted stem cells and from committed T cell progenitors [13].…”

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confidence: 99%

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Making a Notch in the lymphocyte kit

Rodewald

2006

Eur J Immunol

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The receptor tyrosine kinase c-Kit plays crucial roles in lymphocyte development but there is little information on the molecular circuitry enforcing c-Kit expression. In addition to growth factors, Notch signaling is essential for T cell development. In this issue of the European Journal of Immunology, evidence is provided for an interesting link between c-Kit and Notch. The primary 'test subjects' were a Pax5-deficient 'pro-B cell' line, blocked in its B cell potential, and its non-mutated counterpart, a bone marrowderived early progenitor with lymphoid and myeloid potential (EPLM). Similar to common lymphoid progenitors, EPLM have a 'B cell-biased' potential, yet show multipotency under appropriate conditions. Following Notch signaling, c-Kit expression was very rapidly upregulated and the development into T cells was found to be c-Kitdependent. In the absence of Notch signals, c-Kit expression remained low. Development into non-T cell fates (NK or myeloid) was found to be c-Kit-independent. It remains to be determined whether c-Kit is a 'direct' target of the Notch signal transduction pathway; however, these findings, together with those of others, strongly suggest that Notch can contribute to the proper cytokine receptor pattern required for commitment and expansion of early intrathymic progenitors. Cytokines are not only crucial for the regulation of peripheral immune functions but also for the continuous development of hematopoietic cells. In the case of T lymphocytes, two growth factor receptors, the receptor tyrosine kinase c-Kit, and the interleukin 7 receptor (IL-7R), play crucial roles in the expansion and differentiation of progenitor thymocytes (reviewed in [1]). The requirements for signaling via these two receptors are modulated during ontogeny. Up to the fetal and neonatal stages, T cell development is severely reduced but permissive in mice lacking only c-Kit expression (c-Kit W/W ; 'W' for white spotted [2]) or only IL-7R expression, but is completely blocked in doubledeficient mice [3]. This suggests that c-Kit and IL-7R act synergistically during the initial establishment of the T cell compartment. Analysis of the role of c-Kit in adult mice was, for a long time, hampered by the fact that mice homozygous for the natural c-Kit W allele die in the neonatal period [2] owing to severe anemia; however, this defect can be selectively compensated for by transgenic overexpression of erythropoietin [4]. Analyses of these 'W-rescued by epo' ('Wepo') mice has Because of this marked paucity of lymphocyte progenitors in adult c-Kit W/W mice, it has been very difficult to analyze the role of c-Kit in lymphocyte development at the molecular level. As a result, until recently, there was very little information on the signals emanating from c-Kit in early thymocytes; however, the recent generation and analysis of mouse mutants with single amino acid substitutions in c-Kit has revealed the importance of tyrosine 567 in its cytoplasmic tail pointing to a crucial role for this Src binding site in lymphocyte pro...

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mentioning

confidence: 81%

mentioning

confidence: 94%

mentioning

confidence: 95%

“…The study by Massa et al [6] provides evidence for an interesting link between c-Kit and Notch. Interactions between Notch and its ligand (e.g.…”

mentioning

confidence: 97%

mentioning

confidence: 99%

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Making a Notch in the lymphocyte kit

Rodewald

2006

Eur J Immunol

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Molecular Signatures of Highly Malignant Melanoma Stem Cells

Rasheed

2008

Cancer Stem Cells

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The B lineage potential of thymus settling progenitors is critically dependent on mouse age

2007

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The nature and lineage potential, particularly that for B cells, of thymus settling progenitors (TSP) in the adult mouse has been the subject of considerable debate. Lack of B cell potential would suggest pre-thymic, whereas its presence would suggest intrathymic loss of B cell potential. Using limiting dilution analysis (LDA) in vitro and transfer experiments in vivo, we show that the B cell potential of TSP is critically dependent on mouse age, reaching a maximum of about 1 in 20 cells at birth, decreasing 50-fold in adult mice. Cells with a TSP phenotype can be found in the neonatal blood. Furthermore, using LDA, we show that Notch ligand signaling of TSP results in the loss of B cell potential with a half-life of approximately 12 h. Taken together, these results indicate that loss of B cell potential by TSP is an intra-thymic event and highlight the developmental pressure acting on the immune system to rapidly colonize primary lymphoid organs with functional progenitors. This critical time coincides with birth in the mouse. In the adult mouse, we estimate than only about 5 TSP cells/day would be required to maintain steady-state thymopoiesis.

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Critical role for c‐kit (CD117) in T cell lineage commitment and early thymocyte development in vitro

Cited by 74 publications

References 19 publications

Making a Notch in the lymphocyte kit

Making a Notch in the lymphocyte kit

Molecular Signatures of Highly Malignant Melanoma Stem Cells

The B lineage potential of thymus settling progenitors is critically dependent on mouse age

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