Expression pattern of Notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand–receptor interactions in intrathymic T cell development

TLDR

Notch signaling, particularly Notch1 and its mutants, has been implicated in thymocyte differentiation and T‑cell tumorigenesis, prompting investigation into how distinct Notch receptors and ligands shape T‑cell development. Our study shows that Notch1, 2, and 3 receptors and their ligands Jagged1 and Jagged2 are differentially expressed across thymic cell types and developmental stages, with Jagged1 restricted to stromal cells, Jagged2 present in both stromal cells and thymocytes, and Notch3 preferentially up‑regulated in thymocytes interacting with Jagged1/2‑expressing epithelial cells, indicating that Notch3, alongside Notch1, participates in distinct stages of thymocyte maturation.

Abstract

The suggested role of Notch1 or its mutants in thymocyte differentiation and T cell tumorigenesis raises the question of how the different members of the Notch family influence distinct steps in T cell development and the role played by Notch ligands in the thymus. We report here that different Notch receptor–ligand partnerships may occur inside the thymus, as we observed differential expression of Notch1, 2 and 3 receptors, their ligands Jagged1 and 2, and downstream intracellular effectors hairy and Enhancer of Split homolog 1 (HES-1) and hairy and Enhancer of Split homolog 5 (HES-5), depending on ontogenetic stage and thymic cell populations. Indeed, while Jagged2 is expressed in both stromal cells and thymocytes, Jagged1 expression is restricted to stromal cells. Moreover, a differential distribution of Notch3, with respect to Notch1, was observed in distinct age-related thymocyte subsets. Finally, Notch3 was preferentially up-regulated in thymocytes, following the induction of their differentiation by interaction with thymic epithelial cells expressing the cognate Jagged1 and 2 ligands, suggesting that, besides Notch1, Notch3 may also be involved in distinct steps of thymocyte development. Our results suggest that the Notch signaling pathway is involved in a complex interplay of T cell developmental stages, as a consequence of the heterogeneity and specific expression of members of the Notch receptor family and their cognate ligands, in distinct thymic cell compartments.