The potential involvement of Notch signaling in NK cell development.
NK cells constitute an essential element of the innate immune system; however, the cellular and molecular mechanisms that guide their early development are still poorly understood. Here, we demonstrate that in addition to its known crucial role in T cell development, Notch signaling can also be involved in NK cell development. Thus, upon co-culture on OP9 stroma expressing the Notch ligand Delta-like 1 (OP9-DL1), Pax5-deficient pro-B cells, which have multi-lineage potential, efficiently differentiate into T and NK cells. Upon DL-1 signaling, Pax5-deficient pro-B cells down-regulate both surface CD93 expression and transcripts for B cell-specific genes and concomitantly up-regulate T lineage gene transcripts. Subsequent transfer of DL-1-signaled Pax5-deficient pro-B cells onto OP9 stroma in the presence of IL-2 leads to their efficient differentiation into NK1.1(+), functional NK cells. Moreover, bone marrow early progenitor with lymphoid and myeloid differentiation potential (EPLM), which we have previously described as the normal in vivo-equivalent of Pax5-deficient pro-B cells, also gain the ability to differentiate into effector NK cells following transient DL1 Notch-mediated signaling. The potential involvement of Notch signaling in the generation of the NK cell repertoire in vivo is discussed.
Rolink
Antonius G
AG
Department of Clinical and Biological Sciences, Division of Molecular Immunology, Center for Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland. antonius.rolink@unibas.ch
Balciunaite
Gina
G
Demolière
Corinne
C
Ceredig
Rhodri
R
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D018920:Coculture Techniques / Q000379:methods; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D015851:Interleukin-7 / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000502:physiology*; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000378:metabolism; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology
C511877:Dll3 protein, mouse; D007376:Interleukin-2; D015851:Interleukin-7; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051920:NK Cell Lectin-Like Receptor Subfamily D; C497762:Notch1 protein, mouse; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D051881:Receptor, Notch1; D051880:Receptors, Notch