Submitted June 24, 2008
Accepted November 17, 2008
An early decrease in Notch activation is required for human TCR-
lineage differentiation at the expense of TCR-
T cells
Inge Van de Walle, Greet De Smet, Magda De Smedt, Bart Vandekerckhove, Georges Leclercq, Jean Plum, and Tom Taghon*
Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Ghent University Hospital, Ghent, Belgium
* Corresponding author; email: tom.taghon{at}ugent.be.
Although well characterised in the mouse, the role of Notch signalling in the human TCR-
versus TCR-
lineage decision is still unclear. While it is clear in the mouse that TCR- development is less Notch dependent compared to TCR- differentiation, retroviral overexpression studies in human have suggested an opposing role for Notch during human T cell development. Using the OP9-coculture system, we demonstrate that changes in Notch activation are differentially required during human T cell development. High Notch activation promotes the generation of T-lineage precursors and T cells but inhibits differentiation towards the -lineage. Reducing the amount of Notch activation rescues -lineage differentiation, also at the single cell level. Gene expression analysis suggests that this is mediated by differential sensitivities of Notch target genes in response to changes in Notch activation. High Notch activity increases DTX1, NRARP and RUNX3 expression, genes that are downregulated during -lineage differentiation. Furthermore, increased IL-7 levels cannot compensate for the Notch dependent TCR- development. Our results reveal stage-dependent molecular changes in Notch signalling that are critical for normal human T cell development and reveal fundamental molecular differences between mouse and man.
