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  • Review Article
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The different faces of Notch in T-helper-cell differentiation

Nature Reviews Immunology volume 9, pages 116–124 (2009)Cite this article

Key Points

  • Interleukin-12 (IL-12) and IL-4 are widely considered the main inducers of T helper 1 (TH1)- and TH2-cell differentiation, respectively. However, many TH1- and TH2-cell responses in vivo occur in the absence of these cytokines, which suggests that there are other signals that can promote the differentiation of these T-cell lineages.

  • Notch cell-surface receptors have an intracellular domain that acts as a transcription factor following ligand binding of the extracellular domain. The Notch signalling pathway has been implicated in IL-12-independent TH1-cell differentiation and in IL-4-independent TH2-cell differentiation.

  • Notch ligands of the Delta-like ligand (DLL) family promote TH1-cell differentiation in gain-of-function studies and are expressed by antigen-presenting cells (APCs) that induce TH1-cell differentiation. Studies in which the Notch signalling pathway was disabled did not show a defect in TH1-cell responses, but this may have been because the experiments were not carried out under appropriate conditions. DLL proteins seem to have a specific role in IL-12-independent TH1-cell responses.

  • Notch may induce TH1-cell differentiation by directly transactivating Tbx21 (which encodes T-bet), by prolonging the activity of certain nuclear factor-κB family members and by inhibiting IL-4-receptor signalling.

  • Genetic loss-of-function experiments have shown that Notch is required for TH2-cell responses in vivo. The expression of members of the Jagged family of Notch ligands by APCs correlates with the induction of TH2-cell differentiation. In-gain-of function studies, Jagged ligands can promote TH2-cell differentiation, but whether they also mediate this function in vivo has not been established.

  • Notch-mediated TH2-cell differentiation involves direct transcriptional control of the genes encoding the TH2-cell master regulator GATA-binding protein 3 (GATA3) and of Il4.

  • Whether Notch signalling induces TH1- or TH2-cell differentiation may depend on the specific ligand involved (DLL or Jagged). Although the mechanisms are not yet clear, it is possible that the involvement of different Notch proteins with different target gene specificities are important, or that quantitative, qualitative or temporal differences in the activation of Notch signalling by a given Notch receptor could lead to different cellular responses.

Abstract

Interleukin-12 (IL-12) and IL-4 induce T helper 1 (TH1)- and TH2-cell differentiation, respectively, in vitro. However, not all TH1-cell responses require IL-12 in vivo, and TH2-cell responses are remarkably independent of IL-4-receptor signalling, suggesting that other polarizing signals must exist. Accumulating evidence indicates that Notch is a candidate receptor that might mediate these signals. However, contrasting roles for Notch have been proposed: some evidence shows that Notch promotes TH1-cell differentiation, whereas other evidence supports a prominent role for Notch in TH2-cell differentiation. In this Review, we discuss recent findings that help to reconcile this discrepancy and highlight the accumulating evidence for the role of Notch in T-cell-mediated diseases.

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Figure 1: The canonical Notch signalling pathway.
Figure 2: The role of Notch in T-helper-1- and T-helper-2-cell differentiation.

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Acknowledgements

The authors thank F. Manzo for assistance with the preparation of the manuscript. R.A.F. is an investigator of the Howard Hughes Medical Institute. D.A. is supported by an AMC fellowship and a fellowship from the Landsteiner Foundation for Blood Research.

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Authors and Affiliations

  1. Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Derk Amsen

  2. Department of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Andrey Antov & Richard A. Flavell

  3. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Richard A. Flavell

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Glossary

TH17 cell

A type of CD4+ T helper (TH) cell that produces interleukin-17 (IL-17) and that is thought to be important in inflammatory and autoimmune diseases. The generation of TH17 cells involves IL-6 and transforming growth factor-β, as well as the transcription factors RORγt (retinoic-acid-receptor-related orphan receptor-γt) and STAT3 (signal transducer and activator of transcription 3).

γ-secretase complex

A multi-subunit enzyme complex, consisting of presenilin (the catalytic subunit), nicastrin, anterior pharynx defective 1 homologue and presenilin enhancer 2 homologue, that mediates cleavage of transmembrane proteins through a process known as regulated intramembrane proteolysis. In addition to Notch, many other substrates of the γ-secretase complex have been identified, including amyloid precursor protein, CD44, N-cadherin, E-cadherin and v-erb-a erythroblastic leukaemia viral oncogene homologue 4.

Regulatory T (TReg) cell

A specialized type of CD4+ T cell that can suppress the effector responses of other immune cells. TReg cells are crucial for the maintenance of peripheral self tolerance, and a subset of these cells is characterized by the expression of CD25 and the transcription factor forkhead box P3.

Experimental autoimmune encephalomyelitis

An experimental model for the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals through immunization with peptides that are derived from myelin. The animals develop a paralytic disease owing to inflammation and demyelination in the brain and spinal cord.

RNA interference

A method of post-transcriptional control of gene expression, in which the introduction of small, sequence-specific, double-stranded RNAs into cells leads to the degradation of mRNAs that have a complementary sequence.

Chromatin immunoprecipitation

An experimental technique that analyses direct binding of a transcription factor to chromatin by fixation with formaldehyde followed by immunoprecipitation with a transcription-factor-specific antibody. Gene-specific enrichment is then assessed by polymerase chain reaction analysis of the immunoprecipitated DNA.

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Amsen, D., Antov, A. & Flavell, R. The different faces of Notch in T-helper-cell differentiation. Nat Rev Immunol 9, 116–124 (2009). https://doi.org/10.1038/nri2488

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