title: An early decrease in Notch activation is required for human TCR-alphabeta lineage differentiation at the expense of TCR-gammadelta T cells.
abstract: Although well characterized in the mouse, the role of Notch signaling in the human T-cell receptor alphabeta (TCR-alphabeta) versus TCR-gammadelta lineage decision is still unclear. Although it is clear in the mouse that TCR-gammadelta development is less Notch dependent compared with TCR-alphabeta differentiation, retroviral overexpression studies in human have suggested an opposing role for Notch during human T-cell development. Using the OP9-coculture system, we demonstrate that changes in Notch activation are differentially required during human T-cell development. High Notch activation promotes the generation of T-lineage precursors and gammadelta T cells but inhibits differentiation toward the alphabeta lineage. Reducing the amount of Notch activation rescues alphabeta-lineage differentiation, also at the single-cell level. Gene expression analysis suggests that this is mediated by differential sensitivities of Notch target genes in response to changes in Notch activation. High Notch activity increases DTX1, NRARP, and RUNX3 expression, genes that are down-regulated during alphabeta-lineage differentiation. Furthermore, increased interleukin-7 levels cannot compensate for the Notch dependent TCR-gammadelta development. Our results reveal stage-dependent molecular changes in Notch signaling that are critical for normal human T-cell development and reveal fundamental molecular differences between mouse and human.
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital, Ghent, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Van de Walle
authors.forename: Greet
authors.initials: G
authors.lastname: De Smet
authors.forename: Magda
authors.initials: M
authors.lastname: De Smedt
authors.forename: Bart
authors.initials: B
authors.lastname: Vandekerckhove
authors.forename: Georges
authors.initials: G
authors.lastname: Leclercq
authors.forename: Jean
authors.initials: J
authors.lastname: Plum
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000276:immunology / Q000502:physiology; D020869:Gene Expression Profiling; D015329:Gene Rearrangement, T-Lymphocyte / Q000502:physiology; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D015851:Interleukin-7; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D051880:Receptors, Notch