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

Published

Journal Article

Notch1 signalling is essential for the commitment of multipotent lymphocyte precursors towards the alphabeta 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.

Full Text

Duke Authors

Cited Authors

  • Michie, AM; Chan, AC; Ciofani, M; Carleton, M; Lefebvre, JM; He, Y; Allman, DM; Wiest, DL; Zúñiga-Pflücker, JC; Izon, DJ

Published Date

  • December 2007

Published In

Volume / Issue

  • 19 / 12

Start / End Page

  • 1421 - 1430

PubMed ID

  • 17981791

Pubmed Central ID

  • 17981791

Electronic International Standard Serial Number (EISSN)

  • 1460-2377

International Standard Serial Number (ISSN)

  • 0953-8178

Digital Object Identifier (DOI)

  • 10.1093/intimm/dxm113

Language

  • eng