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

Inge Van de Walle (UGent) , Els Waegemans (UGent) , Jelle De Medts (UGent) , Greet De Smet (UGent) , Magda De Smedt (UGent) , SYLVIA SNAUWAERT (UGent) , Bart Vandekerckhove (UGent) , Tessa Kerre (UGent) , Georges Leclercq (UGent) , Jean Plum (UGent) , et al.
(2013) JOURNAL OF EXPERIMENTAL MEDICINE. 210(4). p.683-697
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Abstract
In humans, high Notch activation promotes gamma delta T cell development, whereas lower levels promote alpha beta-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-alpha beta and -gamma delta development, Jagged1 induces mainly alpha beta-lineage differentiation. In contrast, Jagged2-mediated Notch activation primarily results in gamma delta T cell development and represses alpha beta-lineage differentiation by inhibiting TCR-beta formation. Consistently, TCR-alpha beta T cell development is rescued through transduction of a TCR-beta 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 gamma delta T cell development, whereas Notch1 is a weaker activator supporting both TCR-alpha beta and -gamma delta 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-gamma delta differentiation. Our findings reveal that differential Notch receptor-ligand interactions mediate human TCR-alpha beta and -gamma delta T cell differentiation and provide a mechanistic insight into the high Notch dependency of human gamma delta T cell development.
Keywords
PATHWAY, PRECURSORS, ACTIVATION, THYMUS, FATE, B-CELL, T-CELL LINEAGE, BETA-LINEAGE, GAMMA-DELTA, EXPRESSION

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MLA
Van de Walle, Inge, Els Waegemans, Jelle De Medts, et al. “Specific Notch Receptor-ligand Interactions Control Human TCR-αβ/γδ Development by Inducing Differential Notch Signal Strength.” JOURNAL OF EXPERIMENTAL MEDICINE 210.4 (2013): 683–697. Print.
APA
Van de Walle, I., Waegemans, E., De Medts, J., De Smet, G., De Smedt, M., SNAUWAERT, S., Vandekerckhove, B., et al. (2013). Specific Notch receptor-ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength. JOURNAL OF EXPERIMENTAL MEDICINE, 210(4), 683–697.
Chicago author-date
Van de Walle, Inge, Els Waegemans, Jelle De Medts, Greet De Smet, Magda De Smedt, SYLVIA SNAUWAERT, Bart Vandekerckhove, et al. 2013. “Specific Notch Receptor-ligand Interactions Control Human TCR-αβ/γδ Development by Inducing Differential Notch Signal Strength.” Journal of Experimental Medicine 210 (4): 683–697.
Chicago author-date (all authors)
Van de Walle, Inge, 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, and Tom Taghon. 2013. “Specific Notch Receptor-ligand Interactions Control Human TCR-αβ/γδ Development by Inducing Differential Notch Signal Strength.” Journal of Experimental Medicine 210 (4): 683–697.
Vancouver
1.
Van de Walle I, Waegemans E, De Medts J, De Smet G, De Smedt M, SNAUWAERT S, et al. Specific Notch receptor-ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength. JOURNAL OF EXPERIMENTAL MEDICINE. 2013;210(4):683–97.
IEEE
[1]
I. Van de Walle et al., “Specific Notch receptor-ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength,” JOURNAL OF EXPERIMENTAL MEDICINE, vol. 210, no. 4, pp. 683–697, 2013.
@article{4106356,
  abstract     = {In humans, high Notch activation promotes gamma delta T cell development, whereas lower levels promote alpha beta-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-alpha beta and -gamma delta development, Jagged1 induces mainly alpha beta-lineage differentiation. In contrast, Jagged2-mediated Notch activation primarily results in gamma delta T cell development and represses alpha beta-lineage differentiation by inhibiting TCR-beta formation. Consistently, TCR-alpha beta T cell development is rescued through transduction of a TCR-beta 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 gamma delta T cell development, whereas Notch1 is a weaker activator supporting both TCR-alpha beta and -gamma delta 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-gamma delta differentiation. Our findings reveal that differential Notch receptor-ligand interactions mediate human TCR-alpha beta and -gamma delta T cell differentiation and provide a mechanistic insight into the high Notch dependency of human gamma delta T cell development.},
  author       = {Van de Walle, Inge and Waegemans, Els and De Medts, Jelle and De Smet, Greet and De Smedt, Magda and SNAUWAERT, SYLVIA and Vandekerckhove, Bart and Kerre, Tessa and Leclercq, Georges and Plum, Jean and Gridley, Thomas and Wang, Tao and Koch, Ute and Radtke, Freddy and Taghon, Tom},
  issn         = {0022-1007},
  journal      = {JOURNAL OF EXPERIMENTAL MEDICINE},
  keywords     = {PATHWAY,PRECURSORS,ACTIVATION,THYMUS,FATE,B-CELL,T-CELL LINEAGE,BETA-LINEAGE,GAMMA-DELTA,EXPRESSION},
  language     = {eng},
  number       = {4},
  pages        = {683--697},
  title        = {Specific Notch receptor-ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength},
  url          = {http://dx.doi.org/10.1084/jem.20121798},
  volume       = {210},
  year         = {2013},
}

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