Specific Notch Receptor-ligand Interactions Control Human TCR-αβ/γδ Development by Inducing Differential Notch Signal Strength

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2013 Mar 27

PMID 23530123

Citations 53

Authors

Inge Van de Walle

Els Waegemans

Jelle De Medts

Greet De Smet

Magda De Smedt

Sylvia Snauwaert

Bart Vandekerckhove

Tessa Kerre

Georges Leclercq

Jean Plum

Thomas Gridley

Tao Wang

Ute Koch

Freddy Radtke

Tom Taghon

Affiliations

Soon will be listed here.

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.

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