Constitutive Notch signalling promotes CD4(-)CD8(-) thymocyte differentiation in the absence of the pre-TCR complex, by mimicking pre-TCR signals

Michie, A. M. , Chan, A. C., Ciofani, M., Carleton, M., Lefebvre, J. M., He, Y., Allman, D. M., Wiest, D. L., Zuniga-Pflucker, J. C. and Izon, D. J. (2007) Constitutive Notch signalling promotes CD4(-)CD8(-) thymocyte differentiation in the absence of the pre-TCR complex, by mimicking pre-TCR signals. International Immunology, 19(12), pp. 1421-1430. (doi: 10.1093/intimm/dxm113)

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Publisher's URL: http://dx.doi.org/10.1093/intimm/dxm113

Abstract

Notch1 signalling is essential for the commitment of multipotent lymphocyte precursors towards the alpha beta T-cell lineage and plays an important role in regulating beta-selection in CD4(-)CD8(-) double-negative (DN) thymocytes. However, the role played by Notch in promoting the development of CD4(+)CD8(+) double-positive (DP) thymocytes is poorly characterized. Here, we demonstrate that the introduction of a constitutively active Notch1 (ICN1) construct into RAG(-/-) lymphocyte precursors resulted in the generation of DP thymocytes in in vitro T-cell culture systems. Notably, developmental rescue was dependent not only on the presence of an intact Notch1 RAM domain but also on Delta-like signals, as ICN1-induced DP development in RAG(-/-) thymocytes occurred within an intact thymus or in OP9-DL1 co-cultures, but not in OP9-control co-cultures. Interestingly, ICN1 expression in SLP-76(-/-) precursors resulted in only a minimal developmental rescue to the immature CD8(+) single-positive stage, suggesting that Notch is utilizing the same signalling pathway as the pre-TCR complex. In support of this, ICN1 introduction resulted in the activation of the ERK-MAPK-signalling cascade in RAG(-/-) thymocytes. Taken together, these studies demonstrate that constitutive Notch signalling can bypass beta-selection during early T-cell development by inducing pre-TCR-like signals within a T-cell-promoting environment.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Michie, Dr Alison
Authors: Michie, A. M., Chan, A. C., Ciofani, M., Carleton, M., Lefebvre, J. M., He, Y., Allman, D. M., Wiest, D. L., Zuniga-Pflucker, J. C., and Izon, D. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:International Immunology
Publisher:Oxford University Press
ISSN:0953-8178
ISSN (Online):1460-2377
Published Online:01 November 2007
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
444831Defining the cellular origin of chronic lymphocytic leukaemiaAlison MichieMedical Research Council (MRC)G0601099Institute of Cancer Sciences