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Analysis of Notch1 Function by In Vitro T Cell Differentiation of Pax5 Mutant Lymphoid Progenitors¹

Sonja Höflinger^2,*, Kamala Kesavan^2,*, Martin Fuxa^*, Caroline Hutter^*, Barry Heavey^3,*, Freddy Radtke and Meinrad Busslinger^4,*

^* Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria; and Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland

Signaling through the Notch1 receptor is essential for T cell development in the thymus. Stromal OP9 cells ectopically expressing the Notch ligand Delta-like1 mimic the thymic environment by inducing hemopoietic stem cells to undergo in vitro T cell development. Notch1 is also expressed on Pax5^–/– pro-B cells, which are clonable lymphoid progenitors with a latent myeloid potential. In this study, we demonstrate that Pax5^–/– progenitors efficiently differentiate in vitro into CD4⁺CD8⁺ and T cells upon coculture with OP9-Delta-like1 cells. In vitro T cell development of Pax5^–/– progenitors strictly depends on Notch1 function and progresses through normal developmental stages by expressing T cell markers and rearranging TCR, , and loci in the correct temporal sequence. Notch-stimulated Pax5^–/– progenitors efficiently down-regulate the expression of B cell-specific genes, consistent with a role of Notch1 in preventing B lymphopoiesis in the thymus. At the same time, Notch signaling rapidly induces cell surface expression of the c-Kit receptor and transcription of the target genes Deltex1 and pre-T concomitant with the activation of TCR V germline transcription and the regulatory genes GATA3 and Tcf1. These data suggest that Notch1 acts upstream of GATA3 and Tcf1 in early T cell development and regulates V-DJ rearrangements by controlling the chromatin accessibility of V genes at the TCR locus.

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The JI 2004 173: 3579-3580. [Full Text]  

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