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Specific Notch receptor–ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength

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 supp...

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Autores principales: Van de Walle, Inge, Waegemans, Els, De Medts, Jelle, De Smet, Greet, De Smedt, Magda, Snauwaert, Sylvia, Vandekerckhove, Bart, Kerre, Tessa, Leclercq, Georges, Plum, Jean, Gridley, Thomas, Wang, Tao, Koch, Ute, Radtke, Freddy, Taghon, Tom
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620353/
https://www.ncbi.nlm.nih.gov/pubmed/23530123
http://dx.doi.org/10.1084/jem.20121798
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author Van de Walle, Inge
Waegemans, Els
De Medts, Jelle
De Smet, Greet
De Smedt, Magda
Snauwaert, Sylvia
Vandekerckhove, Bart
Kerre, Tessa
Leclercq, Georges
Plum, Jean
Gridley, Thomas
Wang, Tao
Koch, Ute
Radtke, Freddy
Taghon, Tom
author_facet Van de Walle, Inge
Waegemans, Els
De Medts, Jelle
De Smet, Greet
De Smedt, Magda
Snauwaert, Sylvia
Vandekerckhove, Bart
Kerre, Tessa
Leclercq, Georges
Plum, Jean
Gridley, Thomas
Wang, Tao
Koch, Ute
Radtke, Freddy
Taghon, Tom
author_sort Van de Walle, Inge
collection PubMed
description 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.
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spelling pubmed-36203532013-10-08 Specific Notch receptor–ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength Van de Walle, Inge Waegemans, Els De Medts, Jelle De Smet, Greet De Smedt, Magda Snauwaert, Sylvia Vandekerckhove, Bart Kerre, Tessa Leclercq, Georges Plum, Jean Gridley, Thomas Wang, Tao Koch, Ute Radtke, Freddy Taghon, Tom J Exp Med Article 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. The Rockefeller University Press 2013-04-08 /pmc/articles/PMC3620353/ /pubmed/23530123 http://dx.doi.org/10.1084/jem.20121798 Text en © 2013 Van de Walle et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Van de Walle, Inge
Waegemans, Els
De Medts, Jelle
De Smet, Greet
De Smedt, Magda
Snauwaert, Sylvia
Vandekerckhove, Bart
Kerre, Tessa
Leclercq, Georges
Plum, Jean
Gridley, Thomas
Wang, Tao
Koch, Ute
Radtke, Freddy
Taghon, Tom
Specific Notch receptor–ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength
title Specific Notch receptor–ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength
title_full Specific Notch receptor–ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength
title_fullStr Specific Notch receptor–ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength
title_full_unstemmed Specific Notch receptor–ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength
title_short Specific Notch receptor–ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength
title_sort specific notch receptor–ligand interactions control human tcr-αβ/γδ development by inducing differential notch signal strength
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620353/
https://www.ncbi.nlm.nih.gov/pubmed/23530123
http://dx.doi.org/10.1084/jem.20121798
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