title: Specific Notch receptor-ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength.
abstract: In humans, high Notch activation promotes γδ T cell development, whereas lower levels promote αβ-lineage differentiation. How these different Notch signals are generated has remained unclear. We show that differential Notch receptor-ligand interactions mediate this process. Whereas Delta-like 4 supports both TCR-αβ and -γδ development, Jagged1 induces mainly αβ-lineage differentiation. In contrast, Jagged2-mediated Notch activation primarily results in γδ T cell development and represses αβ-lineage differentiation by inhibiting TCR-β formation. Consistently, TCR-αβ T cell development is rescued through transduction of a TCR-β transgene. Jagged2 induces the strongest Notch signal through interactions with both Notch1 and Notch3, whereas Delta-like 4 primarily binds Notch1. In agreement, Notch3 is a stronger Notch activator and only supports γδ T cell development, whereas Notch1 is a weaker activator supporting both TCR-αβ and -γδ development. Fetal thymus organ cultures in JAG2-deficient thymic lobes or with Notch3-blocking antibodies confirm the importance of Jagged2/Notch3 signaling in human TCR-γδ differentiation. Our findings reveal that differential Notch receptor-ligand interactions mediate human TCR-αβ and -γδ T cell differentiation and provide a mechanistic insight into the high Notch dependency of human γδ T cell development.
authors.affiliation: The Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Van de Walle
authors.forename: Els
authors.initials: E
authors.lastname: Waegemans
authors.forename: Jelle
authors.initials: J
authors.lastname: De Medts
authors.forename: Greet
authors.initials: G
authors.lastname: De Smet
authors.forename: Magda
authors.initials: M
authors.lastname: De Smedt
authors.forename: Sylvia
authors.initials: S
authors.lastname: Snauwaert
authors.forename: Bart
authors.initials: B
authors.lastname: Vandekerckhove
authors.forename: Tessa
authors.initials: T
authors.lastname: Kerre
authors.forename: Georges
authors.initials: G
authors.lastname: Leclercq
authors.forename: Jean
authors.initials: J
authors.lastname: Plum
authors.forename: Thomas
authors.initials: T
authors.lastname: Gridley
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Ute
authors.initials: U
authors.lastname: Koch
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology*; D000071656:Receptor, Notch3; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology*; D051880:Receptors, Notch / Q000235:genetics / Q000276:immunology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C490504:JAG2 protein, human; C000606274:Jag1 protein, mouse; C490503:Jag2 protein, mouse; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C499374:NOTCH3 protein, human; C497762:Notch1 protein, mouse; C499373:Notch3 protein, mouse; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins