Notch signaling in the functional differentiation of peripheral CD4+ T-cells

Background: The Notch signalling pathway is a crucial regulator of cell fate decisions in many developmental systems, including T-cell development in the thymus. Recent evidence has established that components of the Notch pathway contribute to the regulation of peripheral immunity and T-cell function. In order to study the function of the Notch ligand Delta 1 in T-cells, we have generated transgenic mice with inducible expression targeted to T-cells. Methods: Transgenic mice were generated using the inducible Tetracycline-On system, with expression of Delta I under the control of the human CD2 promoter. The cell-surface phenotype of peripheral CD4(+) T-cells from transgenic mice was characterized by flow cytometry. In response to in vitro stimulation with anti-CD3/-28 antibodies, the proliferative response of the transgenic T-cells was evaluated by measuring incorporation of tritiated thymidine, and cytokine profiles were determined by ELISA. Results and Conclusions: The induction of the Delta I transgene in CD4(+) T-cells also resulted in enhanced levels of transcripts for Notch 4, Delta 3, Jagged 1 and Hes 1. Compared to controls, the cell surface phenotype of ex vivo transgenic peripheral CD4(+) T-cells was unaltered, whereas following in vitro stimulation with anti-CD3/-28, the expression of CD25 and CD69 was reduced. In addition to a decrease in IL-2 production, transgenic CD4(+)T-cells produce significantly higher levels of IL-10 after stimulation, compared to controls. Therefore, we suggest that the Notch signalling pathway can contribute to functional differentiation of peripheral CD4(+) T-cells and may be a potential therapeutic target for the treatment of allergic diseases.