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.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / immunology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Female
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / immunology
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Jagged-1 Protein
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Jagged-2 Protein
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Male
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Mice
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Receptor, Notch1 / genetics
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Receptor, Notch1 / immunology*
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Receptor, Notch3
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Antigen, T-Cell, alpha-beta / immunology*
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Receptors, Antigen, T-Cell, gamma-delta / genetics
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Receptors, Antigen, T-Cell, gamma-delta / immunology*
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Receptors, Notch / genetics
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Receptors, Notch / immunology*
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Serrate-Jagged Proteins
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocytes / immunology*
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Thymus Gland / cytology
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Thymus Gland / immunology*
Substances
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Calcium-Binding Proteins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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JAG2 protein, human
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Jag1 protein, mouse
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Jag2 protein, mouse
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Jagged-1 Protein
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Jagged-2 Protein
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Membrane Proteins
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NOTCH1 protein, human
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NOTCH3 protein, human
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Notch1 protein, mouse
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Notch3 protein, mouse
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Receptor, Notch1
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Receptor, Notch3
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Antigen, T-Cell, gamma-delta
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Receptors, Notch
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Serrate-Jagged Proteins