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  • Review Article
  • Published:

Regulation of innate and adaptive immunity by Notch

Nature Reviews Immunology volume 13, pages 427–437 (2013)Cite this article

Subjects

Key Points

  • Notch signalling has several important roles in driving both the development and function of cells of the immune system.

  • During lymphocyte development, different Notch ligand and receptor pairs promote commitment to specific cell lineages. Delta-like ligand 4 (DLL4) interacts with Notch 1 to specify thymic T cell commitment, whereas DLL1–Notch 2 signalling promotes lineage commitment in splenic marginal zone B cells. The development of certain subsets of dendritic cells in the spleen and in the lamina propria of the intestine is also dependent on canonical Notch 2 signalling.

  • Notch signalling influences the development and expansion of certain populations of innate lymphoid cells (ILCs), which are a recently described class of innate-like immune cells.

  • Notch signalling is involved in T helper (TH) cell differentiation and function. DLL-mediated Notch signalling favours the development and effector functions of interferon-γ-secreting TH1 cells, whereas Jagged ligands induce the development of TH2 and regulatory T cells.

  • Genetic, pharmacological or antibody-mediated blockade of Notch signalling can reduce the clinical severity of several mouse models of autoimmune disease.

  • Blockade of Notch signalling in allogeneic bone marrow transplantation models inhibits pathological graft-versus-host disease while preserving beneficial graft-versus-tumour effects.This suggest that modulation of Notch signalling could be used to target immune cells during pathological conditions.

Abstract

Coordinated function of the innate and adaptive arms of the immune system in vertebrates is essential to promote protective immunity and to avoid immunopathology. The Notch signalling pathway, which was originally identified as a pleiotropic mediator of cell fate in invertebrates, has recently emerged as an important regulator of immune cell development and function. Notch was initially shown to be a key determinant of cell-lineage commitment in developing lymphocytes, but it is now known to control the homeostasis of several innate cell populations. Moreover, the roles of Notch in adaptive immunity have expanded to include the regulation of T cell differentiation and function. The aim of this Review is to summarize the current status of immune regulation by Notch. A better understanding of Notch function in both innate and adaptive immunity will hopefully provide multiple avenues for therapeutic intervention in disease.

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Figure 1: Notch signalling in immune cell development.
Figure 2: The role of Notch signalling in the development of innate lymphoid cells.
Figure 3: Role of Notch in T helper 1 and T helper 2 cell differentiation and function.

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Acknowledgements

The work in the authors' laboratory is supported in part by the Swiss National Science foundation, the Swiss Cancer League and OptiStem.

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Authors and Affiliations

  1. Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, Lausanne, 1015, Vaud, Switzerland

    Freddy Radtke

  2. Ludwig Center for Cancer Research of the University of Lausanne, Epalinges, 1066, Switzerland

    H. Robson MacDonald

  3. Department of Biochemistry, WHO Immunology Research and Training Center, University of Lausanne, Epalinges, 1066, Switzerland

    Fabienne Tacchini-Cottier

Authors
  1. Freddy Radtke
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  2. H. Robson MacDonald
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  3. Fabienne Tacchini-Cottier
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Corresponding authors

Correspondence to Freddy Radtke, H. Robson MacDonald or Fabienne Tacchini-Cottier.

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RBPJ transcriptional mediator complex

This is the assembly of proteins including RBPJ (known as CSL in humans), the Notch intracellular domain (NICD) and transcriptional co-activators such as Mastermind-like proteins (MAMLs), histone acetyltransferases and the mediator complex in order to generate an active transcriptional complex on target promoters.

β-selection

During development, immature double-negative 3 thymocytes have to pass a critical checkpoint known as β-selection, or the pre-T cell receptor (pre-TCR) checkpoint, at which they have to signal via the pre-TCR to continue their development.

Pre-T cell receptor

(Pre-TCR). The pre-TCR consists of a productively re-arranged TCRβ chain associated with CD3 components and an invariant pre-TCRα chain.

Invariant natural killer T cells

These are a specialized subset of innate-like lymphocytes that share properties of both natural killer (NK) cells and T cells. They express NK-related molecules and T cell receptors (TCRs), and their TCRs recognize self and foreign lipids presented on CD1d molecules.

γ-secretase inhibitors

These are small-molecule inhibitors that block the S3 cleavage of Notch receptors, thereby inhibiting the liberation of the Notch intracellular domain (NICD) and the activation of the Notch signalling cascade.

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Radtke, F., MacDonald, H. & Tacchini-Cottier, F. Regulation of innate and adaptive immunity by Notch. Nat Rev Immunol 13, 427–437 (2013). https://doi.org/10.1038/nri3445

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