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  • Review Article
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Tailoring T-cell receptor signals by proximal negative feedback mechanisms

Key Points

  • T-cell receptor (TCR) signalling is central for the fundamental choice between immunity and tolerance and for regulating T-cell differentiation after exposure to antigen. Signalling circuits control these events by negative and positive mechanisms.

  • The machinery that governs TCR signalling, also known as the TCR signalosome, is composed of three modules that regulate SRC-family protein tyrosine kinases, signal triggering following ligation of the TCR with peptide–MHC complexes and signal diversification for activation of numerous downstream pathways.

  • Novel negative control mechanisms that act rapidly and are generated within the TCR signalosome have been recently uncovered. They are distinct from the regulatory mechanisms that are induced by 'classical' inhibitory receptors such as CD5, CTLA4 (cytotoxic T-lymphocyte antigen 4) and PD1 (programmed cell death 1).

  • Rapid negative feedback mechanisms, such as those activated by the phosphatases SHP1 (SRC-homology-2-domain-containing protein tyrosine phosphatase 1) and the adaptor proteins DOK1 (downstream of kinase 1) and DOK2, might help to explain how T cells reject TCR signal noise that is generated by self ligands and allow ligand discrimination.

  • Other negative feedback mechanisms, such as those activated by the serine/threonine kinase HPK1 (haematopoietic progenitor kinase 1) and the tyrosine phosphatase STS1 (suppressor of T-cell signalling 1), instead seem to modulate signal amplitude once the signal is initiated.

  • When compromised, all the above mechanisms can cause spontaneous autoimmunity or increase the severity of experimentally-induced autoimmune disease.

Abstract

The T-cell receptor (TCR) signalling machinery is central in determining the response of a T cell (establishing immunity or tolerance) following exposure to antigen. This process is made difficult by the narrow margin of self and non-self discrimination, and by the complexity of the genetic programmes that are induced for each outcome. Recent studies have identified novel negative feedback mechanisms that are rapidly induced by TCR engagement and that have key roles in the regulation of signal triggering and propagation. In vitro and in vivo data suggest that they are important in determining ligand discrimination by the TCR and in regulating signal output in response to antigen.

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Figure 1: T-cell receptor signalosome modules and their connections.
Figure 2: Immediate negative feedback control of the T-cell receptor signalosome.
Figure 3: Delayed negative feedback control of the T-cell receptor signalosome.
Figure 4: Dependence of signal amplitude and kinetics on stimuli strength and consequences on biological outcomes.

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Acknowledgements

We thank the Wellcome Trust Foundation and the Sir William Dunn School of Pathology for financial support to the Acuto laboratory, and the Institut Pasteur, the Centre National de la Recherche Scientifique and the Association pour la Recherche sur le Cancer for financial support to V.D.B. and F.M. V.D.B. is also funded by the Ligue National Contre le Cancer, the European Union (MUGEN Network of Excellence; LSGH-CT-2005-005,203) and the Agence Nationale de la Recherche. We apologize for not being able to cite more extensively the literature on this subject owing to space limitations. Finally, we thank A. van der Merwe, M. Salek and K. Nika for reading the manuscript and providing feedback.

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Correspondence to Oreste Acuto.

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Additional negative regulators of T–cell–receptor–induced signalling (PDF 475 kb)

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Glossary

Calcium signalling

Calcium signalling is triggered by phospholipase Cγ1-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate into inositol-1,4,5-trisphosphate (InsP3) and diacylglycerol. InsP3 then binds its receptor on the endoplasmic reticulum (ER) membrane to cause the release of calcium from ER stores. This leads to the opening of calcium-release-activated calcium channels in the plasma membrane and the influx of calcium ions. The increased intracellular calcium concentration activates calcineurin, protein kinase C and several other enzymes that are required for gene expression.

Immunological synapse

A region that can form between two cells of the immune system that are in close contact. The name derives from similarities to the synapses that occur in the nervous system. The immunological synapse refers to the interaction between a T cell or natural killer cell and an antigen-presenting cell. This interface involves adhesion molecules, as well as antigen receptors and cytokine receptors.

SRC family

A group of structurally related cytoplasmic and/or membrane-associated enzymes that are named after the prototypical member, SRC. In haematopoietic cells, SRC-family kinases — such as LCK, FYN and LYN — are the first protein tyrosine kinases that are involved in signalling following stimulation through the immunoreceptors. They phosphorylate ITAMs that are present in the signal-transducing subunits of the immunoreceptors, thereby providing binding sites for SRC-homology-2-domain-containing molecules, such as SYK and ZAP70.

Immunoreceptor tyrosine-based activation motifs

(ITAMs). Short peptide motifs containing tyrosine residues that are found in the cytoplasmic tail of several signalling adaptor proteins and that are necessary to recruit proteins that are involved in triggering activating signalling pathways. The consensus sequence is Tyr-X-X-(Leu/Ile)-X6–8-Tyr-X-X-(Leu/Ile), where X denotes any amino acid.

Glycolipid-enriched membrane microdomains

(GEMs). Specialized membrane domains that are enriched in cholesterol and glycosphingolipids, and proteins that function in signal transduction. GEMs are also known as membrane rafts or detergent-insoluble glycosphingolipid-enriched membrane microdomains.

Ubiquitylation

The attachment of the polypeptide ubiquitin to lysine residues in cellular proteins. Ubiquitylation is catalysed by ubiquitin ligases, the expression of which may be developmentally regulated or induced by particular stimuli. It has an important role in the regulation of intracellular trafficking, and the degradation of receptors and signalling effectors.

Immunoreceptor tyrosine-based inhibitory motifs

(ITIMs). Short peptide motifs containing a tyrosine residue that are found in the cytoplasmic regions of many inhibitory receptors. The consensus sequence is (Ile/Val/Leu/Ser)-X-Tyr-X-X-(Leu/Val), where X denotes any amino acid. Following tyrosine phosphorylation by SRC-family protein tyrosine kinases, ITIMs provide a high-affinity docking site for the recruitment of cytoplasmic phosphatases and other signalling molecules with an appropriate SRC homology 2 domain.

Dual-specificity phosphatase

An enzyme that catalyses the dephosphorylation of tyrosine, and serine or threonine residues in proteins.

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Acuto, O., Bartolo, V. & Michel, F. Tailoring T-cell receptor signals by proximal negative feedback mechanisms. Nat Rev Immunol 8, 699–712 (2008). https://doi.org/10.1038/nri2397

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