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

Irma Tindemans,Marlies J. W. Peeters,Rudi W. Hendriks

doi:10.3389/fimmu.2017.00419

Irma Tindemans, Marlies J. W. Peeters + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2017.00419

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Abstract

For protection against pathogens, it is essential that naïve CD4+ T cells differentiate into specific effector T helper (Th) cell subsets following activation by antigen presented by dendritic cells (DCs). Next to T cell receptor and cytokine signals, membrane-bound Notch ligands have an important role in orchestrating Th cell differentiation. Several studies provided evidence that DC activation is accompanied by surface expression of Notch ligands. Intriguingly, DCs that express the delta-like or Jagged Notch ligands gain the capacity to instruct Th1 or Th2 cell polarization, respectively. However, in contrast to this model it has also been hypothesized that Notch signaling acts as a general amplifier of Th cell responses rather than an instructive director of specific T cell fates. In this alternative model, Notch enhances proliferation, cytokine production, and anti-apoptotic signals or promotes co-stimulatory signals in T cells. An instructive role for Notch ligand expressing DCs in the induction of Th cell differentiation is further challenged by evidence for the involvement of Notch signaling in differentiation of Th9, Th17, regulatory T cells, and follicular Th 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 Notch receptors on CD4+ T cells and the impact of Notch ligands on antigen-presenting cells.

Highlights

Following signals from both antigen-presenting cells (APCs) and the micro-environment, activated CD4+ T cells are triggered to initiate secretion of specific effector cytokines
Most studies using bmDCs would support an instructive role for Jagged in the induction of Th2 cell differentiation and function (Table 1), our studies indicate that induction of Th2 responses in house dust mite (HDM)-driven airway inflammation (AAI) is dependent on Jagged expression on other cell types than dendritic cells (DCs) or alternatively on cooperation between Jagged and delta-like ligands (DLL) on DCs
We found that Jagged expression was required for the induction of a Th2 response in the lung when in vitro HDM-pulsed bmDCs were used for allergen sensitization, but not when mice were in vivo sensitized by endogenous airway DCs [32]

Summary

INTRODUCTION

Following signals from both antigen-presenting cells (APCs) and the micro-environment, activated CD4+ T cells are triggered to initiate secretion of specific effector cytokines. Since the original observation in 1986 upon antigenic stimulation naive CD4+ T cells can differentiate into T helper 1 (Th1) or Th2 effector T cells depending on polarizing cytokine signals [1], various additional Th subsets have been recognized. These include Th9, Th17, Th22, follicular T helper cells (Tfh), and regulatory T cells (Tregs), each characterized by a unique cytokine production profile and a key transcription factor [see for recent review Ref. We will focus on both Notch receptor expressing T cells and Notch ligand-expressing cells

THE NOTCH SIGNALING PATHWAY

INDUCTION OF NOTCH LIGANDS ON APCs

Cockroach allergen

Other T Helper Cell Subsets

CONCLUSIONS AND FUTURE DIRECTIONS