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

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Abstract
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.