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Molecular mechanisms of CD4+ T-cell anergy

Key Points

  • In vitro clonal T-cell anergy is induced in previously activated T cells or T-cell clones by restimulation through the T-cell receptor (TCR) in the absence of co-stimulatory signals. This suboptimal signalling produces long-lived effects, such as reduced proliferation and cytokine production.

  • Early molecular studies of anergic T cells found reduced amounts of the activator protein 1 (AP1) heterodimer in the nucleus coupled with normal translocation to the nucleus of nuclear factor of activated T cells (NFAT). Subsequent evidence suggested the requirement for calcium flux and the potential for expression of proteins enriched specifically by the anergic programme to induce T-cell anergy.

  • Recent work identified important roles for linker for activation of T cells (LAT) palmitoylation, diacylglycerol (DAG) signalling, and transcription factors for the induction of both in vitro and in vivo T-cell anergy.

  • Using the calcium ionophore ionomycin to simulate calcium flux and promote NFAT nuclear translocation without co-stimulation events, a group of E3 ubiquitin ligases — Casitas B-lineage lymphoma B (CBL-B), gene related to anergy in lymphocytes (GRAIL) and ITCH (itchy homologue E3 ubiquitin protein ligase) — were found to be enriched in anergic T cells. These members of the ubiquitin–proteasome pathway were also identified in other model systems of in vitro and in vivo T-cell anergy, and their ability to induce T-cell anergy depends on their E3 ubiquitin ligase activity.

  • CBL-B ubiquitylation affects various signalling pathways including the phosphoinositide 3-kinase (PI3K) pathway, VAV1-mediated actin reorganization, and TCR downregulation. GRAIL-mediated ubiquitylation stabilizes expression of an inhibitor of the RHO family and has potent effects on T-cell activation. ITCH expression attenuates phospholipase Cγ1 (PLCγ1) activation by monoubiquitylation and targets the JUN family of transcription factors for degradation.

  • As these E3 ubiquitin ligases contain disparate structural elements, subcellular localization and substrate targets, it is likely that they function at different levels of T-cell activation. Combining their effects together in an additive manner shunts T cells away from activation and towards T-cell anergy.

Abstract

Directing both innate and adaptive immune responses against foreign pathogens with correct timing, location and specificity is a fundamental objective for the immune system. Full activation of CD4+ T cells requires the binding of peptide–MHC complexes coupled with accessory signals provided by the antigen-presenting cell. However, aberrant activation of the T-cell receptor alone in mature T cells can produce a long-lived state of functional unresponsiveness, known as anergy. Recent studies probing both immune signalling pathways and the ubiquitin–proteasome system have helped to refine and elaborate current models for the molecular mechanisms underlying T-cell anergy. Controlling anergy induction and maintenance will be a key component in the future to mitigate unwanted T-cell activation that leads to autoimmune disease.

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Figure 1: A comparison between signalling pathways in fully stimulated and in anergized T cells.
Figure 2: Two recent additions to the mechanism of anergy induction.
Figure 3: Structural domains of the anergy-associated E3 ubiquitin ligases.
Figure 4: A model for regulation of T-cell activation by three E3 ubiquitin ligases following anergy induction.

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Acknowledgements

We apologize to all those researchers who have made contributions to the field of T-cell tolerance and anergy but were not discussed due to space restrictions. We thank L. Su and the editors for discussions and critical reading of the manuscript. Supported by the National Institutes of Health, USA, grants CA65237 and DK078123.

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Glossary

Central tolerance

The lack of self-responsiveness that occurs during lymphocyte development in the central lymphoid organs. B-cell progenitors in the bone marrow and T-cell progenitors in the thymus that strongly recognize self antigen either undergo further rearrangement of antigen-receptor genes to avoid reactivity to self or face deletion by apoptosis.

Peripheral tolerance

The lack of self-responsiveness of mature lymphocytes in the periphery to specific antigens. These mechanisms can control potentially self-reactive lymphocytes that have escaped central tolerance or prevent immune responses to specialized self proteins that were not present during establishment of central tolerance. Peripheral tolerance is associated with suppression of self-reactive antibody production by B cells and inhibition of self-reactive effector cells, such as cytotoxic T lymphocytes.

E3 ubiquitin ligase

An enzyme that attaches ubiquitin to substrate proteins. Single subunit E3 ubiquitin ligases contain both the substrate-binding domain(s) and E2-tranferase recruitment machinery in the same polypeptide chain, whereas multisubunit E3 ubiquitin ligases divide these functions between individual protein components. E3 ubiquitin ligases are further classified on the basis of their E2-transferase recruitment domains: HECT-type, RING-finger-type and U-box-type.

Adaptive tolerance

Also known as in vivo anergy, this phenomenon results from the challenge of T cells in the periphery by either superantigen or specific peptides that results in T-cell activation in the absence of upregulated co-stimulation on antigen-presenting cells. This state differs from in vitro clonal T-cell anergy in many ways, most notably in its requirement for persistent antigen presentation to maintain the anergic state.

Activator protein 1

(AP1). A transcription factor heterodimer of FOS and JUN that is formed following T-cell activation and is critically important for inducing the transcription of interleukin-2.

Cyclosporin A

An immunosuppressive drug that inhibits calcineurin, a Ca2+-dependent serine/threonine phosphatase necessary for the nuclear translocation of the transcription factor NFAT (nuclear factor of activated T cells).

Guanine-nucleotide-exchange factor

(GEF). A protein that stimulates the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) on small GTPases, resulting in activation of the GTPase.

Heterokaryon

Any cell with more than one nucleus and the nuclei of which are not all of the same genetic constitution. The term heterokaryon can also refer to a tissue composed of such cells.

Superantigen

A microbial protein that activates all T cells expressing a particular set of T-cell receptor (TCR) Vβ chains by crosslinking the TCR to a particular MHC regardless of the peptide presented.

Immunological synapse

A region that can form between two cells of the immune system in close contact. The immunological synapse originally referred to the interaction between a T cell and an antigen-presenting cell. It involves adhesion molecules, as well as antigen receptors and cytokine receptors.

Small interfering RNA

(siRNA). Synthetic RNA molecules of 19–23 nucleotides that are used to 'knockdown' (that is, silence the expression of) a specific gene. This is known as RNA interference (RNAi) and is mediated by the sequence-specific degradation of mRNA.

Detergent-resistant microdomains

(DRMs). Cell-membrane extracts that are enriched in cholesterol, phospholipids and sphingolipids, which are liquid ordered yet insoluble in non-ionic detergents. They are often referred to as lipid rafts, which provide ordered structure to the lipid bilayer and have the ability to include or exclude specific signalling molecules and complexes.

Ubiquitin-binding proteins

Proteins that contain one of the structurally diverse domains that can directly bind (generally with weak to moderate affinity) to ubiquitin attached to substrates. These domains include the ubiquitin-interacting motif (UIM), the ubiquitin associated (UBA) domain and the ubiquitin-conjugating enzyme variant (UEV) domain.

Ionomycin

A calcium ionophore from Streptomyces conglobatus that induces the release of intracellular calcium stores.

OTU domain

(Ovarian tumour domain). A domain that is found in a large family of proteins characterized by the presence of a putative catalytic triad of cysteine proteases. Several of these proteins are known to function as deubiquitylating or ubiquitin-modifying enzymes.

Agouti locus

The agouti locus on mouse chromosome 2 determines the coat colour of a mouse by regulating the synthesis of yellow pigment by hair melanocytes. Mutations in this locus are also linked to immunological defects and the development of obesity and neoplasms.

C2 domain

A versatile interaction domain that binds a wide variety of substrates including various lipids, calcium ions and phosphotyrosine residues.

WW domain

A protein–protein interaction module that contains two conserved tryptophan (W) residues that are 20–22 amino acids apart and that interacts with proline-rich motifs.

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Fathman, C., Lineberry, N. Molecular mechanisms of CD4+ T-cell anergy. Nat Rev Immunol 7, 599–609 (2007). https://doi.org/10.1038/nri2131

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