Notch Receptor-Ligand Interactions During T Cell Development, a Ligand Endocytosis-Driven Mechanism

Abstract

Notch signaling plays an important role during the development of different cell types and tissues. The role of Notch signaling in lymphocyte development, in particular in the development and commitment to the T cell lineage, has been the focus of research for many years. Notch signaling is absolutely required during the commitment and early stages of T cell development. Activation of the Notch signaling pathway is initiated by ligand-receptor interactions and appears to require active endocytosis of Notch ligands. Studies addressing the mechanism underlying endocytosis of Notch ligands have helped to identify the main players important and necessary for this process. Here, we review the Notch ligands, and the proposed models of Notch activation by Notch ligand endocytosis, highlighting key molecules involved. In particular, we discuss recent studies on Notch ligands involved in T cell development, current studies aimed at elucidating the relevance of Notch ligand endocytosis during T cell development and the identification of key players necessary for ligand endocytosis in the thymus and during T cell development.

Notch1 is an important mediator for enhancing of B‐cell activation and antibody secretion by Notch ligand

“…Intrathymic T‐cell development is also critically affected by signalling through Notch1, and members of two families of structurally distinct Notch ligands, Delta‐like 1 and Jagged‐1, are expressed by thymic epithelial cells and thymocytes . Many Notch receptors have specific roles in each step of T‐cell differentiation in the thymus . Some reports suggest that peripheral T‐cell activation can also be regulated by Notch signalling; for example, CSL‐mediated Notch signalling enhances T‐cell proliferation in the presence of antigen‐presenting cells, and induces preferential polarization toward the T helper type 2 (Th2) lineage, while simultaneously inhibiting Th1 cell differentiation .…”

“…11,12 Many Notch receptors have specific roles in each step of T-cell differentiation in the thymus. [13][14][15][16] Some reports suggest that peripheral T-cell activation can also be regulated by Notch signalling; for example, CSLmediated Notch signalling enhances T-cell proliferation in the presence of antigen-presenting cells, and induces preferential polarization toward the T helper type 2 (Th2) lineage, while simultaneously inhibiting Th1 cell differentiation. 17 In addition, recent findings show that Notch affects Th17 cell differentiation.…”

IL-18 Acts in Synergy with IL-7 To Promote Ex Vivo Expansion of T Lymphoid Progenitor Cells

“…Notch signaling plays a crucial role in directing T cell development by tightly regulating various developmental steps including commitment, selection, proliferation, and survival of differentiating thymocytes (42). For instance, Notch can promote the proliferation and survival of DN populations by positively regulating the growth promoting signal pathways mediated by IL-7R and c-Kit (33, 43).…”

Cellular-Defined Microenvironmental Internalization of Exosomes

“…Endocytosis, while not a primary function of T cells, is important to T cell receptor signaling [76] as well as other functions. Dynamin-dependent endocytosis [76], phagocytosis [77], and RME [78] are some of the mechanisms involved in T cell interaction with its surrounding environment. In relation to exosomes, T cells operate through RME [17,79,80] and lipid raft-dependent endocytosis [75].…”