Abstract
Recent reports suggested that Delta1, 4 and Jagged1, 2 possessed the ability to instruct CD4+ T cell into selection of Th1 or Th2 fates, respectively, although the underlying mechanism endowing the cleaved Notch receptor with memory of ligand involved in its activation remains elusive. To examine this, we prepared artificial antigen-presenting cells expressing either DLL1 or Jag1. Although both ligands were efficient in inducing Notch2 cleavage and activation in CD4+ T or reporter cells, the presence of Lunatic Fringe in CD4+ T cells inhibited Jag1 activation of Notch1 receptor. Neither ligand could induce Th1 or Th2 fate choice independently of cytokines or redirect cytokine-driven Th1 or Th2 development. Instead, we find that Notch ligands only augment cytokine production during T cell differentiation in the presence of polarizing IL-12 and IL-4. Moreover, the differentiation choices of naïve CD4+ T cells lacking γ-secretase, RBP-J, or both in response to polarizing cytokines revealed that neither presenilin proteins nor RBP-J were required for cytokine-induced Th1/Th2 fate selection. However, presenilins facilitate cellular proliferation and cytokine secretion in an RBP-J (and thus, Notch) independent manner. The controversies surrounding the role of Notch and presenilins in Th1/Th2 polarization may reflect their role as genetic modifiers of T-helper cells differentiation.
Highlights
Naive CD4+ T cells can acquire at least four distinct phenotypes following activation by antigen, including three distinct types of effectors, Th1, Th2 and Th17 cells and various subsets of regulatory T cells [1,2,3,4,5,6,7]
Among the factors that influence the choice of the naıve T cells toward these distinct fates, cytokines produced by antigen presenting cells (APCs) exert powerful effects that promote or restrict these choices [4,8,9,10,11,12]
Under conditions where polarizing cytokines were neutralized, neither DLL1 nor Jag1 led to significant changes in IFN-c or IL-4 production (Figure 2A, B), indicating that these ligands are not sufficient for driving Th1 or Th2 fate choice. These data are inconsistent with the results reported for DLL1 and Jag1 expression on DCEK hi7 fibroblasts as artificial APCs [30], which claimed DLL1 and Jag1 to induce Th1 and Th2 development, respectively
Summary
Naive CD4+ T cells can acquire at least four distinct phenotypes following activation by antigen, including three distinct types of effectors, Th1, Th2 and Th17 cells and various subsets of regulatory T cells [1,2,3,4,5,6,7]. Among the factors that influence the choice of the naıve T cells toward these distinct fates, cytokines produced by antigen presenting cells (APCs) exert powerful effects that promote or restrict these choices [4,8,9,10,11,12]. In addition to cytokine signaling pathways, many other factors have been proposed to regulate these choices [6,22,23,24,25,26,27,28]. Recent studies have suggested that distinct Notch ligands expressed on APCs might regulate Th1 and Th2 fate choice [29,30,31,32]. Notch proteins are membrane-bound receptors that regulate diverse cell fate decisions in multi-cellular organisms [33]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
