Abstract
Notch signaling provides an important cue in the mammalian developmental process. It is a key player in T cell development and function. Notch ligands such as Delta-like ligands (DLL) 1, 3, 4, and JAG1, 2 can impact Notch signaling positively or negatively, by trans-activation or cis-inhibition. Trans and cis interactions are receptor-ligand interaction on two adjacent cells and interaction on the same cell, respectively. The former sends an activation signal and the later, a signal for inhibition of Notch. However, earlier reports suggested that Notch is activated in the absence of Notch ligand-expressing APCs in a purified population of CD4 T cells. Thus, the role of ligands in Notch activation, in a purified population of CD4 T cells, remains obscure. In this study, we demonstrate that mature CD4 T cells are capable of expressing Notch ligands on their surface very early upon activation with soluble antibodies against CD3 and CD28. Moreover, signaling solely through CD28 induces Notch ligand expression and CD3 signaling inhibits ligand expression, in contrast to Notch which is induced by CD3 signaling. Additionally, by using decoys, mimicking the Notch extracellular domain, we demonstrated that DLL1, DLL4, and JAG1, expressed on the T cells, can cis-interact with the Notch receptor and inhibit activation of Notch. Thus, our data indicate a novel mechanism of the regulation of Notch ligand expression on CD4 T cells and its impact on activated Notch.
Highlights
Notch signaling is one of the most conserved signaling pathways in eukaryotes and is critical throughout development in vertebrates as well as in invertebrates [1]
Activation of T cells by antibody cross-linking of the CD3ε chain of the TCR complex and CD28 leads to the activation of Notch1, through γ- secretase mediated cleavage and release of the Notch intracellular domain (ICD) [10,11,12]
To determine the potential role of the Notch ligands DLL1, DLL4, and JAG1 in purified CD4 T cells we investigated the kinetics of Notch ligand expression following signaling through TCR and CD28
Summary
Notch signaling is one of the most conserved signaling pathways in eukaryotes and is critical throughout development in vertebrates as well as in invertebrates [1]. There are four different Notch receptors found in mammals, Notch. Canonical Notch ligands fall into a category called Delta/Serrate/Lag-2 (DSL) ligands, named for their conserved DSL like domain. The ligands in mammals can be categorized into two groups, homologs of Drosophila Notch ligands Delta or Serrate. The Delta like ligands (DLL) in mammals are DLL1, DLL3, and DLL4 and Serrate like ligands are JAG1 and JAG2 [3, 4]. In addition to containing a DSL domain, all five vertebrate ligands possess extracellular epidermal growth factor (EGF) like repeats. The mature Notch receptor consists of an extracellular (ECD) with EGF like repeats, a transmembrane (TM) and an intracellular domain (ICD).
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