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  • Review Article
  • Published:

The role of TNF superfamily members in T-cell function and diseases

Nature Reviews Immunology volume 9, pages 271–285 (2009)Cite this article

Key Points

  • Several interactions that occur between tumour necrosis factor (TNF) superfamily members have gained prominence based on studies of animal models of immune function and disease. The interactions between OX40 ligand (OX40L) and OX40, 4-1BBL and 4-1BB, CD70 and CD27, and TL1A and death receptor 3 (DR3), positively regulate T-cell responses and mediate crosstalk between T cells and other cell types.

  • A feature of the molecules in these four ligand–receptor pairs is that they are not ubiquitously expressed. The finding that their expression is increased following immune-cell activation suggests that they have a central role in modulating immune responses.

  • There is not a simple set of rules that determines when and where these molecules are expressed, and hence in which context they are important for T-cell responses. Their expression can be upregulated by T cells, antigen-presenting cells, natural killer (NK) cells, NKT cells, as well as activated endothelial cells and peripheral tissue cells. The expression of some of these molecules in normal and disease conditions in humans has been documented, and numerous reports suggest a correlation between expression and disease status or sometimes therapy outcome.

  • A primary function of the TNF superfamily molecules is to regulate cell survival. In addition, signals from OX40, 4-1BB, CD27 and DR3 also synergize with T-cell receptor (TCR) signals to allow cell cycle progression, thereby promoting T-cell division and cytokine production by T cells.

  • There are two main approaches for therapy based on targeting TNF–TNF receptor (TNFR) interactions: one is to block their interactions to reduce pathogenic immune responses in autoimmune and inflammatory diseases; the second is to enhance signalling triggered by the TNFR to stimulate a more robust immune response, which would be useful for promoting antitumour immunity.

  • Preclinical studies have analyzed the activities of neutralizing antibodies that are specific for TNF ligands, or of Fc fusion proteins that contain a TNFR molecule that binds to the ligand and thereby blocks the endogenous interaction. The effects of blocking each of the four ligand–receptor interactions discussed in this article have been assessed with promising results in models of inflammatory diseases (including allergy, asthma, transplantation, graft-versus-host disease and atherosclerosis) and autoimmune diseases (including experimental autoimmune encephalomyelitis, diabetes, colitis, adjuvant or collagen-induced arthritis, and systemic lupus erythematosus).

  • Numerous mouse studies have investigated the effectiveness of agonist antibodies to the TNFRs in tumour models or the effects of stimulatory Fc fusion proteins that express the extracellular portion of TNF ligands that cross-link the TNFRs. These have shown strong antitumour activity, which has been largely associated with increased effector activity of CD4+ and/or CD8+ T cells, as well as NK and NKT cells.

Abstract

Interactions that occur between several tumour necrosis factor (TNF)–TNF receptors that are expressed by T cells and various other immune and non-immune cell types are central to T-cell function. In this Review, I discuss the biology of four different ligand–receptor interactions — OX40 ligand and OX40, 4-1BB ligand and 4-1BB, CD70 and CD27, and TL1A and death receptor 3 — and their potential to be exploited for therapeutic benefit. Manipulating these interactions can be effective for treating diseases in which T cells have an important role, including inflammatory conditions, autoimmunity and cancer. Here, I explore how blocking or inducing the signalling pathways that are triggered by these different interactions can be an effective way to modulate immune responses.

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Figure 1: TNF–TNFR family interactions and molecular targets in T cells and APCs.
Figure 2: Control of T-cell proliferation by cooperative and sequential TNF–TNFR interactions.
Figure 3: TNF–TNFR family interactions regulate many cell types to amplify inflammation.
Figure 4: Modulation of TReg-cell development and function by TNF–TNFR interactions.

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Acknowledgements

M.C. is supported by grants AI67341, CA91837, AI49453 and AI070535 from the National Institutes of Health.

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    Michael Croft

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Glossary

Regulatory T (TReg) cell

A specialized T cell that suppresses the effector immune responses of other immune cells and is crucial for the maintenance of peripheral tolerance. One CD4+ TReg-cell subset is characterized by the expression of the transcription factor forkhead box P3 (FOXP3), whereas other types of TReg cell are normally characterized based on their expression of immunosuppressive cytokines such as interleukin-10 and transforming growth factor-β.

Lymphoid-tissue inducer cell

A cell that is present in developing lymph nodes, Peyer's patches and nasopharynx-associated lymphoid tissue. Lymphoid-tissue inducer cells are required for the development of these lymphoid organs. Adult lymphoid-tissue inducer cells have been proposed to orchestrate the development of tertiary lymphoid structures during inflammatory responses.

Graft-versus-host disease

(GVHD). A disease that results from the immunological attack by donor allogeneic T cells that are transferred along with the allograft (such as bone marrow, liver or gut allografts) of target recipient organs or tissues (such as the skin and gut). GVHD occurs in graft recipients that cannot eliminate the host-reactive donor T cells owing to immunosuppression, immunological immaturity or tolerance of the recipient.

Experimental autoimmune encephalomyelitis

(EAE). An animal model of the human autoimmune disease multiple sclerosis. EAE is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies that are specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B- and T-cell function.

Antibody-dependent cell-mediated cytotoxicity

A cytotoxic mechanism by which an antibody-coated target cell is directly killed by a leukocyte that expresses Fc receptors, such as a natural killer (NK) cell, macrophage or neutrophil. A specific receptor for the Fc region of IgG is CD16, which is expressed on the surface of most NK cells. Following binding to immunoglobulin, CD16 initiates a signalling cascade that results in the release of cytotoxic granules (containing perforin and granzyme B), which induce apoptosis of the antibody-coated cell.

Complement-dependent cytotoxicity

A mechanism by which a monoclonal antibody binds complement, leading to direct cell toxicity and complement-mediated killing of the cell to which the antibody is bound. The result is a membrane attack complex that makes a hole within the cell membrane, causing cell lysis and death.

Tolerance

A term that denotes lymphocyte non-responsiveness to antigen, but implies an active process, not simply a passive lack of response.

RNA aptamer

An oligonucleotide sequence that has the ability to recognize virtually any class of target molecules with high affinity and specificity. RNA aptamers are emerging as a class of molecules that rival antibodies in terms of therapeutic and diagnostic applications. They provide some advantages over antibodies, as they can be produced by chemical synthesis, have better storage properties and are less immunogenic.

Cytokine storm

A sudden surge in the circulating levels of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, tumour necrosis factor and interferon-γ.

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Croft, M. The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol 9, 271–285 (2009). https://doi.org/10.1038/nri2526

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