Making a Notch in the lymphocyte kit

Abstract

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...

Macrophage and T‐lymphocyte Infiltrates in Human Peritoneal Adhesions Indicate a Chronic Inflammatory Disease

“…Regarding tissue regeneration, the Notch‐3, β‐catenin, and c‐myc pathways have been proven to be fundamental cell‐signaling pathways of proliferation and differentiation responses during normal development and wound healing [43, 44]. In accord with this finding, a marked expression of Notch‐3, β‐catenin, and c‐myc could be verified in the present investigation.…”

Phenotypic plasticity of T cell progenitors upon exposure to Notch ligands

“…It has been suggested that one critical effect of Notch signaling during early T cell development might be the up-regulation or maintenance of c-kit expression on precursor cells ultimately leading to similar c-kit surface expression ( 22 ), which is required for developmental progression along the T cell lineage ( 23 ). When comparing CLP-1 and CLP-2 cells with regard to c-kit and Flt3 ligands, we found that Flt3L had a greater impact than SCF on the survival and expansion of CLP-1 cells early during developmental progression, although both receptors, Flt3 and c-kit, were differentially expressed on CLP-1 and CLP-2 cells.…”

Influence of 4% icodextrin solution on peritoneal tissue response and adhesion formation

“…The C-myc and catenin pathways are known for their important role in tissue remodelling, wound healing and regeneration [35,36]. The low expression in our experimental setting might indicate that the C-myc and catenin pathways are not appropriate markers in order to illustrate peritoneal repair mechanisms.…”