Notch Signaling in T Helper Cell Subsets: Instructor or Unbiased Amplifier?

For protection against pathogens, it is essential that naive CD4+ T cells differentiate into specific effector T helper (Th) cell subsets following activation by antigen presentedby dendritic cells (DCs). Next to T cell receptor and cytokine signals, membrane-bound Notchligands have an important role in orchestrating Th cell differentiation. Several studies provided evidence that DC activation is accompanied by surface expression of Notchligands. Intriguingly, DCs that express the Delta-like or Jagged Notchligands gain the capacity to instruct Th1 or Th2 cell polarization, respectively. However, in contrast to this model it has also been hypothesized that Notchsignaling acts as a general amplifier of Th cell responses rather than an instructive director of specific T cell fates. In this alternative model Notchenhances proliferation, cytokine production and anti-apoptotic signals or promotes co-stimulatory signals in T cells. An instructive role for Notchligand expressing DCs in the induction of T helper celldifferentiation is further challenged by evidence for the involvement of Notchsignaling in differentiation of Th9, Th17, regulatory T cells and follicular T helper cells. In this review, we will discuss the two opposing models, referred to as the ‘instructive’ and the ‘unbiased amplifier’ model. We highlight both the function of different Notchreceptors on CD4+ T cells and the impact of Notchligands on antigen-presentingcells.