Critical role for c-kit (CD117) in T cell lineage commitment and early thymocyte development in vitro.
The precise roles played by the transmembrane receptor tyrosine kinase c-kit and its ligand stem cell factor in early T cell development are difficult to study. Using cloned Pax5-deficient progenitor B cells, we show that following Notch signaling, which induces their commitment to the T cell developmental pathway, c-kit expression is rapidly up-regulated at both the transcriptional and cell surface level. Using either an anti-c-kit monoclonal antibody or Gleevec, a pharmacological inhibitor of c-kit signaling, we show that the Notch-induced T cell differentiation of either Pax5-deficient progenitor B cells, or the equivalent cell from the bone marrow of normal mice, is strictly dependent on c-kit signaling, whereas the differentiation of normal progenitors into the B cell lineage is not. Moreover, we show that the Notch and IL-7 signaling-induced proliferation and differentiation of CD44+CD25-c-kit(high) and CD44+CD25+c-kithigh thymocytes along the T cell, but not natural killer cell or macrophage, pathway also requires c-kit signaling, whereas the Notch-induced proliferation and differentiation of CD44-CD25+c-kitint cells along the T cell pathway is independent of c-kit. These results further highlight the complex inter-relationships existing between c-kit, Notch and IL-7 receptor signaling that control the proliferation and differentiation of early T cell progenitors.
Developmental and Molecular Immunology, Department of Clinical and Biological Sciences (DKBW), Center for Biomedicine, University of Basel, Basel, Switzerland.
Steffen
S
Massa
Gina
G
Balciunaite
Rhodri
R
Ceredig
Antonius G
AG
Rolink
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology; D001549:Benzamides; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D018960:Hyaluronan Receptors / Q000276:immunology; D000068877:Imatinib Mesylate; D015851:Interleukin-7 / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D051379:Mice; D051757:PAX5 Transcription Factor / Q000172:deficiency / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology*; D011743:Pyrimidines / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D051880:Receptors, Notch / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013234:Stem Cells / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
D000911:Antibodies, Monoclonal; D001549:Benzamides; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D015851:Interleukin-7; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D015375:Receptors, Interleukin-2; D051880:Receptors, Notch; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit