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

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.

Figures

Figure 1. TnF–TnFR family interactions and molecular targets in T cells and APCs

Tumour necrosis factor receptors (TNFRs) are characterized by several cysteine-rich domains, and TNF ligands are characterized by a TNF homology domain. Both OX40 ligand (OX40L) and TL1A are homotrimers (that is, three receptor monomers bind to the trimeric ligand), and this molecular arrangement probably applies to interactions between CD70 and CD27, 4-1BBL and 4-1BB, and TL1A and death receptor 3 (DR3). During interactions between T cells and antigen-presenting cells (APCs), the expression of TNF ligands by the APC is probably induced following activating signals from either CD40 (when bound to CD40L expressed by a T cell) or from Toll-like receptor (TLR)-mediated signals. The ligation of cytokine receptors by cytokines such as TNF, interleukin-1 (IL-1), IL-6, IL-12, IL-18 and thymic stromal lymphopoietin (not shown) can also promote TNF ligand expression. The expression of OX40 and 4-1BB can be induced by activation signals from the T-cell receptor (TCR) following recognition of peptide–MHC complexes. The main common downstream signalling event triggered by TNFRs is the activation of nuclear factor-κB 1 (NF-κB1), which leads to cell division and enhanced survival and can contribute to the production of cytokines, such as IL-2, IL-4, IL-5 and interferon-γ (IFNγ). NF-κB2 can also be activated downstream of these TNFRs, although its primary function in cellular responses is not clear. Other signalling molecules that have been described to be activated following TNF-–TNFR interactions include phosphoinositide 3 kinase (PI3K), protein kinase B (PKB), extracellular-signal-regulated kinase (ERK), JUN N-terminal kinase (JNK) (not shown) and nuclear factor of activated T cells (NFAT) (not shown), which also contribute to cell division, survival and cytokine production. Triggering of any TNFR might lead to the expression of other proteins that promote proliferation, including survivin, aurora B kinase, cyclins and cyclin-dependent kinases (CDKs), as well as the expression of anti-apoptotic proteins, including BCL-2 (B-cell lymphoma 2), BCL-XL, BFL1 (BCL-2-related protein A1), and/or the downregulation of the expression of pro-apoptotic proteins, such as BIM (BCL-2-interacting mediator of cell death). Signals downstream of the TNF ligands can promote the secretion of pro-inflammatory cytokines by APCs, such as TNF, IL-1, IL-6 and IL-12, and lead to cellular proliferation.

Figure 2. Control of T-cell proliferation by cooperative and sequential TNF–TNFR interactions

A hallmark of T-cell co-stimulation by the tumour necrosis factor receptors (TNFRs) OX40, 4-1BB, CD27 or DR3 is the expansion of the effector T-cell population (during the primary response and/or the secondary and memory response). However, the extent of cooperation between these individual ligand–receptor pairs over the course of most T-cell responses is not clear. Three non-mutually exclusive models that represent what might occur are shown. The involvement of the TNFRs probably varies depending on the inflammatory environment in which antigen recognition takes place and the nature and number of antigens recognized. a| Step-wise involvement of TNFRs, whereby the temporal activity of individual receptors increases and sustains T-cell survival and proliferation. In this case, the interactions of all of the different TNFRs with their ligands are crucial for generating large effector T-cell populations, and inhibiting any one will markedly suppress the response. b| A more complex scenario that involves synergistic action of different TNFRs, whereby several ligand–receptor interactions can function simultaneously, as well as sequentially. In this case, continued T-cell survival and proliferation depend on a threshold level of signalling imparted by multiple receptors. Removing any single interaction would, again, markedly reduce the response. c| A scenario that might explain the involvement of TNFRs in promoting a T-cell response when many antigens or autoantigens are expressed. Several populations that express different TNFRs would be involved in the response (including CD4+ and CD8+ T cells specific for various epitopes). If only one population is involved, blocking a single TNF–TNFR interaction would suppress the response, although which interactions are involved probably varies. However, when several T-cell populations are active, pronounced suppression would require targeting two or more interactions. DR3, death receptor 3.

Figure 3. TNF–TNFR family interactions regulate many cell types of amplify inflammation

Effector T cells receive signals for division, survival and cytokine production following the activation of the tumour necrosis factor receptors (TNFRs) OX40, 4-1BB, CD27 and death receptor 3 (DR3) by their ligands. In addition, natural killer (NK) and NKT cells can also receive signals through TNFRs that amplify division, survival and cytokine production. The initiation of inflammatory responses can involve cooperation between NK and NKT cells with effector T cells, which might occur directly or indirectly through antigen-presenting cells (APCs). Feedback mechanisms can occur through NK- or NKT-cell-derived interferon-γ (IFNγ), which enhances APC activation in many ways, including promoting the expression of TNF ligands. In addition, activated mast cells can express many ligands, including OX40 ligand (OX40L) and 4-1BBL, which can co-stimulate effector T cells and NKT cells. The production of pro-inflammatory cytokines, such as IFNγ, interleukin-13 (IL-13) and IL-17, by T cells also can promote the expression of one or several TNF ligands on tissue cells such as endothelial, epithelial and smooth muscle cells. Through additional bidirectional signals with effector T cells, NK cells or NKT cells, these interactions probably further amplify tissue pathology, for example, by inducing the production of additional pro-inflammatory mediators such as leukotrienes and histamine. CTL, cytotoxic T cell; NKG2D, NK group 2, member D; TH, T helper; ULBP3, cytomegalovirus UL16-binding protein.

Figure 4. modulation of TReg-cell development and function by TNF–TNFR interactions

In addition to promoting the activation of effector T cells, the interaction between the tumour necrosis factor receptors (TNFRs) OX40, 4-1BB, CD27 and DR3 and their ligands might further contribute to inflammation by affecting naturally occurring or inducible regulatory T (TReg) cells. To date, only the effect of OX40 or 4-1BB ligation on TReg-cell development and function has been examined, although the fact that the different receptors can use common signalling pathways (including the nuclear factor-κB and protein kinase B pathways) means that it is possible that DR3 and CD27 have similar effects. Signals triggered following the activation of OX40 inhibit the expression of forkhead box P3 (FOXP3) and interleukin-10 (IL-10) by naive CD4+ T cells that are differentiating into TReg cells by an unknown mechanism, which might involve blocking or modulation of the signalling events downstream of transforming growth factor-β receptor (TGFβR), IL-10R or vitamin D receptor (not shown). OX40 can also reduce the stability of TReg cells, as ligation of OX40 can lead to the downregulation of FOXP3 and IL-10 expression in recently differentiated TReg cells. This may occur directly, or indirectly through promoting the production of cytokines by T helper cells, which in turn induce the expression of transcription factors such as GATA-binding protein 3 that prevent FOXP3 and/or IL-10 expression (not shown). Fully differentiated inducible CD4+ and CD8+ TReg cells and natural CD4+ TReg cells also express OX40, 4-1BB, CD27 and DR3. OX40 and 4-1BB signals have been shown to block the suppressive function of these cells, again either directly through effects on the TReg cell itself, or indirectly by promoting the proliferation and survival of effector T cells and by rendering them resistant to TReg-cell-mediated suppression. The combined action of these TNF–TNFR interactions might lead to an increased ratio of effector T cells to TReg cells (that is, too few TReg cells to suppress the inflammatory response) and/or to greater effector T-cell activity through blocking of TReg-cell-mediated suppression. Activation of the TNFRs might also promote the expansion or survival of TReg cells (not shown), as shown in some in vitro systems with agonist stimulation, although studies of knockout animals do not as yet support this expansion as a physiological activity. DR3, death receptor 3.