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  • Review Article
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Notch signalling during peripheral T-cell activation and differentiation

Nature Reviews Immunology volume 7, pages 64–75 (2007)Cite this article

Key Points

  • Notch transmembrane receptors (Notch1, Notch2, Notch3 and Notch4 in mammals) are evolutionarily conserved proteins that mediate cell-fate decisions in many systems during embryogenesis and postnatal development, including the immune system.

  • During thymocyte development, Notch proteins regulate binary cell-fate choices at crucial checkpoints, including T-cell- versus B-cell-specific gene expression, αβ versus γδ T-cell-receptor expression, and CD4+ versus CD8+ lineage decisions.

  • Notch signalling in mammals is triggered by five canonical ligands: Jagged1, Jagged2, Delta-like 1 (DLL1), DLL3 and DLL4. Additional, non-canonical ligands have also been described, which indicates that there are additional mechanisms of initiating Notch signalling at the cell surface.

  • Notch proteins interact with the canonical nuclear binding partner CSL (CBF1-suppressor of hairless–Lag1; known as RBP-J in mice), to convert a transcriptional repressor complex to an activating complex by displacing co-repressors and recruiting co-activators.

  • Notch proteins have been shown to interact with members of the nuclear factor-κB (NF-κB) family of transcription factors to regulate expression of the gene encoding interferon-γ and other genes.

  • Potential roles for Notch proteins in the activation and differentiation of peripheral T cells to T helper 1 (TH1), TH2 and regulatory T cells have been described, which indicates that manipulation of Notch signalling might prove to be beneficial for the treatment of certain autoimmune conditions, or in the context of transplantation.

Abstract

For many years, researchers have focused on the contribution of Notch signalling to lymphoid development. Only recently have investigators begun to ask what role, if any, Notch has during the activation and differentiation of naive CD4+ T cells in the periphery. As interest in this issue grows, it is becoming increasingly clear that the main role of Notch signalling, to regulate cell-fate decisions, might also be influential in peripheral T cells.

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Figure 1: Notch expression and activation.
Figure 2: Canonical pathway of Notch signalling through CSL.
Figure 3: Possible consequences of Notch signalling.
Figure 4: The role of Notch proteins in peripheral T cells.

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Acknowledgements

We wish to thank members of the Osborne laboratory for comments and conversations, and R. Goldsby for critical review and support. We also thank L. Miele and T. Golde for continued collaborations and discussions over the past several years. We apologize to all of those investigators whose data could not be cited owing to space considerations. B.A.O. and L.M.M. are supported by grants from the United States National Institute of Allergy and Infectious Diseases and National Institute of Aging.

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  1. Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, 01003, Massachusetts, USA

    Barbara A. Osborne & Lisa M. Minter

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Correspondence to Barbara A. Osborne.

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Glossary

T helper 1/T helper 2 cells

(TH1/TH2 cells). Functional subsets of CD4+ T cells expressing an αβ T-cell receptor that produce either type 1 cytokines (interleukin-2 (IL-2), interferon-γ and other cytokines that support macrophage activation, the generation of cytotoxic T cells and the production of opsonizing antibodies) or type 2 cytokines (IL-4, IL-5, IL-13 and other cytokines that support B-cell activation, the production of non-opsonizing antibodies, allergic reactions and the expulsion of extracellular parasites).

Fucosylation

Addition of the sugar fucose to the oligosaccharide chains (glycans) of membrane proteins through the enzymatic actions of a particular fucosyltransferase.

S1-cleavage site

A specific site in the Notch pre-protein that is targeted by a furin-like protease in the trans-Golgi during the maturation of Notch proteins.

Glycosylation

Enzymatic addition of carbohydrate groups to the side chains of asparagine, serine or threonine residues. This process is important in the synthesis of many secreted and cell-surface proteins.

Trans-endocytosis

The process by which a tightly associated receptor–ligand complex induces invagination of the plasma membrane and internalization of the complex into the ligand-bearing cell to form a membrane-limited transport vesicle.

ADAM proteases

(A disintegrin and metalloproteinase family of proteases). Members of this family contain disintegrin-like and metalloproteinase-like domains and are involved in the regulation of developmental processes, cell–cell interactions and protein processing, including ectodomain shedding.

S2-cleavage site

A specific site in the extracellular domain (close to the membrane) of the Notch heterodimer that becomes accessible to ADAM proteases, which cleave the Notch protein, after ligand binding.

S3-cleavage site

A cleavage site in the transmembrane region (cytoplasmic side) of Notch proteins. Cleavage is thought to occur in endosomes, after cleavage at the S2 site, by a complex of proteins that have γ-secretase activity. In mouse Notch1, this site lies between amino-acid residues 1743 and 1744.

Histone acetyl transferases

Proteins that mediate the enzymatic addition of an acetyl group to the amino group of an amino-terminal residue of the histone complex to facilitate transcription.

Cre–loxP approach

A site-specific recombination system. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Expression of the recombinase Cre leads to excision of the intervening sequence. Depending on the type of promoter that controls Cre expression, Cre can be expressed at specific times during development or by specific subsets of cells.

Tolerization

Acquired or induced tolerance describes a lack of responsiveness by the immune system to exogenous antigens, a state that is normally created through experimental manipulation. It is important in organ transplantation, when the body is 'forced' to accept an organ from another individual.

Linked suppression

The phenomenon of suppressing immune responses to a specific antigen by co-presenting it simultaneously with another antigen, against which tolerance has previously been established.

Graft-versus-host response

A deleterious process during which immunocompetent donor cells contained in transplanted tissue recognize immunosuppressed host tissues as 'foreign' and mount a destructive immune response against them.

Graft-versus-malignancy response

Similar to a graft-versus-host response, but the cells targeted for destruction in the host are tumorigenic or leukaemic.

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Osborne, B., Minter, L. Notch signalling during peripheral T-cell activation and differentiation. Nat Rev Immunol 7, 64–75 (2007). https://doi.org/10.1038/nri1998

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