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Molecular mechanisms of T cell co-stimulation and co-inhibition

An Erratum to this article was published on 05 June 2013

This article has been updated

Key Points

  • Co-stimulatory and co-inhibitory molecules are cell surface receptors and ligands that are classified into various families on the basis of their structure and functions.

  • After interaction with their specific ligands or counter-receptors that positively and negatively regulate T cell function, co-signalling receptors trigger biochemical signals in T cells.

  • Multiple co-stimulatory and co-inhibitory receptors are expressed differentially during specific phases of T cell differentiation and on specific subsets of T cells to direct T cell regulation and function.

  • Co-stimulatory and co-inhibitory molecules constitute important targets for immune modulation and the treatment of human diseases.

Abstract

Co-stimulatory and co-inhibitory receptors have a pivotal role in T cell biology, as they determine the functional outcome of T cell receptor (TCR) signalling. The classic definition of T cell co-stimulation continues to evolve through the identification of new co-stimulatory and co-inhibitory receptors, the biochemical characterization of their downstream signalling events and the delineation of their immunological functions. Notably, it has been recently appreciated that co-stimulatory and co-inhibitory receptors display great diversity in expression, structure and function, and that their functions are largely context dependent. Here, we focus on some of these emerging concepts and review the mechanisms through which T cell activation, differentiation and function is controlled by co-stimulatory and co-inhibitory receptors.

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Figure 1: Co-signalling interactions in T cells.
Figure 2: Co-stimulatory and co-inhibitory signalling pathways downstream of CD28 family receptors.
Figure 3: Co-signalling pathways downstream of tumour necrosis factor receptor superfamily receptors.

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Change history

  • 05 June 2013

    In Figure 1a of the original version of this article, the indicated expression of CD40 and CD40L was incorrect. CD40 should instead be shown on the antigen presenting cell (APC) and CD40L on the T cell. This has now been corrected online. Nature Reviews Immunology apologizes for this error.

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Acknowledgements

The authors thank B. Cadugan for editing the manuscript. The work in the authors laboratory has been supported by US National Institutes of Health (NIH) grants CA142779, CA121974, CA97085, CA16359, CA86721, AI72592 and the Melanoma Research Alliance.

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Supplementary information

Supplementary S1 (Table)

IgSF T cell co-stimulatory and co-inhibitory receptors (PDF 122 kb)

Supplementary S2 (Table)

TNFRSF co-stimulatory and co-inhibitory molecules (PDF 111 kb)

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Glossary

Two-signal model

Activation of naive T cells requires two signals: T cell receptor (TCR) signalling and co-stimulatory signalling. TCR signalling following interaction with peptide–MHC complexes confers specificity to T cell activation but results in T cell unresponsiveness in the absence of co-stimulatory signalling, which synergizes with TCR signalling.

Immunological synapse

A large junctional structure that is formed following the initial T cell receptor recognition of cognate peptide–MHC complexes on antigen-presenting cells. This structure, which is composed of central and peripheral supra-molecular activation clusters (SMACs), is crucial for the spatial organization of surface interactions, cytoplasmic signalling components and scaffolds.

Trans-endocytosis

A process whereby material from one cell, such as cell surface molecules and portions of the cell membrane, enters or is endocytosed by another cell. This process is often referred to as trogocytosis when cell surface components are physically trans-endocytosed following cellular interactions.

Affinity

The strength of binding of one molecule to another molecule. It is represented by the dissociation constant (Kd), which is the concentration of one molecule required to occupy half of the binding sites of a second molecule.

Bi-directional co-signalling

When two interacting molecules on two different cells both function as receptors and transduce a signal into their respective cell.

Indoleamine 2,3-dioxygenase

(IDO). An intracellular haem-containing enzyme that catalyses the oxidative catabolism of tryptophan. Insufficient availability of tryptophan can lead to T cell apoptosis and anergy.

T follicular helper cells

(TFH cells). Antigen-experienced CD4+ T cells expressing CXC-chemokine receptor 5 (CXCR5)+ and B cell lymphoma 6 (BCL6)+. TFH cells are found in the B cell follicles of secondary lymphoid organs, and they induce germinal centre formation and regulate germinal centre B cell activation and function.

TNF receptor-associated factor

(TRAF). A family of conserved adaptor proteins containing a C-terminal domain that interacts with tumour necrosis factor receptor superfamily and other cell surface receptors and an N-terminal domain that links receptors with downstream signalling events.

Non-canonical NF-κB signalling

A pathway that requires the activation of the nuclear factor-κB (NF-κB)-inducing kinase (NIK) to process the NF-κB2 precursor protein p100 into a mature p52 subunit, which then dimerizes with RelB (RelB–p52) to regulate a distinct pattern of gene expression compared to the canonical pathway, which relies on RelA–p50 dimers.

Sanroque mice

A mouse strain that carries a loss-of-function mutation in the gene roquin, a zinc finger transcription factor that represses inducible T cell co-stimulator (ICOS) mRNA. These mice therefore overexpress ICOS and have a T cell-mediated systemic-lupus-erythematosus-like syndrome and severe autoimmune diabetes when on a susceptible genetic background.

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Chen, L., Flies, D. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 13, 227–242 (2013). https://doi.org/10.1038/nri3405

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