TNF superfamily members have diverse functions in mammalian biology and are often expressed by cells of the immune system. TNF superfamily members are important therapeutic targets for the treatment of autoimmune disease and for encouraging tumour clearance.
Dendritic cells (DCs) are the most potent antigen-presenting cells in the immune system. DC-intrinsic signals can dictate whether T cells respond or show tolerance to an antigen.
The expression of TNF superfamily receptors and ligands by T cells and DCs suggests an important role for this molecular superfamily in T cell–DC crosstalk. TNF superfamily receptors on T cells can provide co-stimulation for the T cell response when they interact with their corresponding TNF superfamily ligands that have been upregulated on DCs.
TNF superfamily receptors that are expressed directly on DCs can provide homeostatic signals to the DCs in the steady state and can function to 'license' the DCs during an immune response by virtue of T cell–DC crosstalk. Licensed DCs secrete pro-inflammatory cytokines and express CD70.
Modulation of TNF superfamily receptor-derived signals in the gut can have a dramatic impact on mucosal inflammation and responses to mucosal pathogens. In the gut, T cell–DC crosstalk may be replaced by communication between DCs and innate lymphoid cells to provoke protective immunity and to maintain tolerance to the resident microbial communities in this location.
Members of the tumour necrosis factor (TNF) superfamily have been implicated in a wide range of biological functions, and their expression by cells of the immune system makes them appealing targets for immunomodulation. One common theme for TNF superfamily members is their coordinated expression at the interface between antigen-specific T cells and antigen-presenting dendritic cells and, by virtue of this expression pattern, TNF superfamily members can shape T cell immune responses. Understanding how to manipulate such functions of the TNF superfamily may allow us to tip the balance between immunity and tolerance in the context of human disease.
The tumour necrosis factor (TNF) superfamily is a large family of molecules that have diverse roles in mammalian biology1. Most TNF superfamily ligands and receptors are expressed by cells of the immune system and are often induced during immune activation. As such, these molecules are appealing 'drugable targets'; indeed, inhibitors and agonists of various TNF superfamily pathways are in development or actively being prescribed in the clinic to treat autoimmune diseases and to eradicate cancers (Table 1). Since 1988, biennial meetings have brought together scientists and trainees from industry and academia to illuminate the therapeutic potential of targeting TNF superfamily members and to unravel the roles of these molecules in mammalian biology (see the 14th International TNF Conference website).
As there is significant therapeutic potential in manipulating dendritic cell (DC)–T cell interactions for the treatment of complex diseases, this Review focuses on how TNF superfamily members influence various aspects of DC biology. We discuss how TNF superfamily members affect the maintenance of DCs and lymphoid tissues in the steady state, the maturation and activation of DCs during an immune response, and the function of DCs at mucosal surfaces, and we consider how TNF superfamily members can be exploited in the context of DC-targeted therapies. Furthermore, we provide an integrative model for how inputs from different TNF superfamily receptors can shape T cell responses. As therapies directed at modifying DC function gain promise in the clinic, an understanding of how TNF superfamily members influence DC biology will provide new avenues of treatment for significant health problems.
TNF superfamily members and lymphoid tissue
Members of the TNF superfamily have diverse roles in mammalian biology, including in the maintenance of leukocyte subsets and the survival of mature B cells, and this has been recently reviewed2. Although a discussion on how TNF superfamily members control the survival and homeostasis of lymphocytes is beyond the scope of this Review, in this section we describe TNF superfamily receptor-mediated signals that are crucial for shaping the priming environment that sets the stage for T cell–DC crosstalk. We begin with the lymphoid tissue itself.
The TNF superfamily and lymphoid tissue development. T cell–DC crosstalk occurs within the complex microenvironment of secondary lymphoid organs. For peripheral antigens, this crosstalk occurs in lymph nodes; for orally ingested antigens, it occurs in the Peyer's patches of the gut; and for blood-borne antigens, it occurs in the spleen. The development of secondary lymphoid organs requires signalling through the lymphotoxin-β receptor (LTβR), a TNF superfamily receptor that is triggered by lymphotoxin-α (LTα)–LTβ heterotrimers (LTαβ). This concept has been recently reviewed3,4, and it is highly relevant to the overarching role of TNF superfamily members in coordinating effective humoral and cellular immunity, especially in the generation of high-affinity antibodies that can confer long-term immunological memory against pathogens. In brief, in developing secondary lymphoid organs, populations of non-lymphoid LTβR-expressing radio-resistant cells (known as lymphoid-tissue organizer cells) interact with LTαβ-expressing radio-sensitive lymphoid-tissue inducer cells. Coordinate interactions between lymphoid-tissue organizer cells and lymphoid-tissue inducer cells result in chemokine production and the formation of an emerging lymph node anlage.
The TNF superfamily and lymphoid tissue maintenance. In adult mice, LTβR-expressing radio-resistant stromal cells also support and regulate ongoing immune responses, and directly influence T cell–DC crosstalk. The characterization of stromal cells is an emerging field, and various stromal cell subtypes perform distinct functions. For example, specialized stromal cells can be found at locations of antigen entry into lymphoid tissue; these locations include the subcapsular sinuses of lymph nodes, the subepithelial domes of Peyer's patches and the marginal zone of the spleen. In addition to supporting the development of secondary lymphoid organs in utero, constitutive LTβR signalling is required to maintain the organization of secondary lymphoid organ microenvironments and the population of these niches by antigen-presenting and antigen-transporting cells5. For example, subcapsular sinus macrophages, which shuttle antigens into the lymph nodes, are LT sensitive6, as are marginal zone macrophages of the spleen. In the domes of Peyer's patches, DCs require signalling through the TNF superfamily receptor RANK (receptor activator of NF-κB), and microfold cells, which shuttle antigens into the subepithelial lamina propria of the gut, require RANK and 4-1BB signalling1,7. Thus, TNF superfamily members are important for maintaining the microenvironments that promote the transfer of antigens into the lymphoid tissue parenchyma for further presentation to T cells.
In addition to maintaining stromal environments that support antigen transport, the LTαβ–LTβR pathway is important for regulating the entry of naive lymphocytes into lymph nodes. The portals of entry into lymph nodes are high endothelial venules (HEVs). The radio-resistant cells of these venules must be maintained in a 'mature' state to accommodate the entry of naive lymphocytes, and LTβR signalling is crucial for HEV maturation8. The expression of LTαβ has been best characterized on activated lymphocytes, where it is required for the maintenance of chemokine expression by LTβR-expressing stromal cells in lymphoid tissues. However, recombination activating gene (RAG)-deficient mice, which lack B and T cells, were found to have normal HEVs, suggesting that a non-lymphocyte source of LTαβ is required for HEV maturation. Intriguingly, a recent study has shown that expression of LTαβ by lymph node-resident DCs is important for HEV maturation, thus providing an explanation for why RAG-deficient mice have normal HEVs and also suggesting that there is direct communication between DCs and HEVs9.
Downstream of their entry through HEVs, lymphocytes must home to their correct niches within lymphoid tissues. The stromal cells that support T cell–DC interactions are fibroblastic reticular cells (FRCs), whereas follicular dendritic cells (FDCs) are an important scaffold for B cell follicles and germinal centres. Such stromal cells have a variety of functions in fine-tuning both immunity and tolerance, and the LT pathway is important for maintaining chemokine production by such stromal cells to orchestrate cell–cell interactions during immune responses5. Indeed, in the absence of LTβR signalling, segregation between T cell and B cell zones is not maintained, and the lymphoid tissue becomes highly disorganized10. Signalling via CD30 — a TNF superfamily receptor that is expressed by activated lymphocytes — is also required to maintain adequate T cell–B cell segregation in the spleen11. Thus, TNF superfamily members are important for setting up the stromal cell 'space' in which T cell–DC interactions occur.
The TNF superfamily and lymph node hypertrophy. TNF superfamily members are important for supporting lymph node hypertrophy. Inflammation provokes lymph node hypertrophy, whereby lymphocyte recruitment through HEVs and DC migration into the subcapsular sinus are maximized and lymphocyte egress into the medullary cords is limited. These conditions increase the odds of cognate T cell–DC encounters. DCs can induce the proliferation of vascular endothelial cells to support draining lymph node hypertrophy103. Vascular endothelial growth factor (VEGF) is an important mediator of inflammation-driven lymph node hypertrophy and has a key role in endothelial cell proliferation104. FRCs are an important source of this growth factor during lymphangiogenesis, and the production of VEGF by FRCs depends on LTβR signalling13. However, VEGF can be produced by various sources and, indeed, lymphangiogenesis depends on complex interactions between different cell types, including DCs, B cells and T cells14. TNF is another important mediator of lymph node hypertrophy, and it has been suggested that tissue-resident mast cells are a major source of this TNF105. It is possible that such a 'remote-control' mechanism may also be involved in modifying vascular endothelial cells and HEVs (for example, cytokines and other growth factors could be transmitted via lymph node conduits), but this remains unclear. Both TNF and LTα bind to TNF receptor 1 (TNFR1) and TNFR2, and LTα is important for lymphangiogenesis in tertiary lymphoid structures15, suggesting that TNF and LTα have complementary roles depending on the anatomical location of the lymphangiogenesis process. Finally, it was shown that lymph node hypertrophy is also dependent on the TNF superfamily member LIGHT12, which signals through LTβR, and it has been speculated that the relevant source of LIGHT is tissue-derived Langerhans cells.
In summary, complex cellular interactions that rely on signals derived from TNF superfamily receptors must take place within secondary or tertiary lymphoid tissues to promote lymphangiogenesis. As the number of DCs that enter a draining lymph node can have a direct effect on the magnitude and quality of the immune response16, lymphangiogenesis is an important control mechanism for ensuring optimal immune responses. Furthermore, the same signals that are important for lymphangiogenesis may be required for lymphoid tissue remodelling post-infection. Indeed, this is the case for LTβR-dependent signals in the spleen17 and lymph nodes7 following lymphocytic choriomeningitis virus (LCMV) infection.
The TNF superfamily and DC maintenance. As mentioned above, DCs have an important role in regulating the entry of naive lymphocytes into lymph nodes. However, the main function ascribed to DCs is to capture antigens and present them to T cells (Box 1). There are several distinct DC subsets, and each subset has specialized functions and a unique anatomical location (Table 2). The TNF superfamily ligands TNF18 and CD40 ligand (CD40L)19 can promote the proliferation of bone marrow-derived progenitor cells and their differentiation into DCs. Following their egress from the bone marrow, DCs in lymphoid tissues have a short lifespan, with 50% of this population turning over in a 1–3 day period, and this turnover rate is also influenced by TNF superfamily members. For example, RANK20,21 and CD40 (Ref. 22) promote DC survival during an active immune response. However, as neither RANK ligand (RANKL)-deficient mice23 nor CD40-deficient mice24 exhibit a deficit in peripheral DCs, the effect of these molecules may be limited to enhancing DC survival during an ongoing immune response, or perhaps these pathways are mutually redundant in the steady state. Recent data have shown that, during inflammation, 4-1BB-mediated signalling in DCs may promote DC survival by inducing the upregulation of the anti-apoptotic molecules B cell lymphoma XL (BCL-XL) and BCL-2 (Ref. 25). This is a different scenario from that found in the steady state, in which 4-1BB appears to limit DC development and restrict the number of peripheral mature DCs26. As 4-1BB ligand (4-1BBL) is generally not expressed in the absence of inflammation, it is possible that 4-1BB exerts an inducible effect on DCs during an immune response.
Focusing on DC survival, LT-deficient mice exhibit a marked reduction in DC numbers in the steady state27. In addition to being expressed by stromal cells, LTβR is expressed by DCs, and signalling occurs following the binding of membrane-bound LTαβ or LIGHT (Box 2). Kabashima et al. showed that LTβR-deficient mice selectively lack CD11b+CD8− DCs. Given the important function of the LT pathway in regulating the expression of chemokines and adhesion molecules28, it was assumed that such a DC deficit was due to a problem with DC migration into lymphoid tissues. However, using elegant chimeric approaches and parabiotic mice, it was shown that the requirement for LTβR in maintaining CD11b+ DC numbers was DC intrinsic and that signalling via LTβR was important for DC proliferation29. The expression of LTαβ on B cells was required for inducing homeostatic DC proliferation, which makes sense given the fact that splenic CD11b+ DCs are enriched in the marginal zone, where marginal zone B cells are plentiful. However, it is possible that upregulation of LTαβ on antigen-activated T cells could also provoke DC proliferation in the context of an immune response and, indeed, enforced expression of the alternative ligand LIGHT on T cells was shown to stimulate DC proliferation in vitro and in vivo30. It is likely that the interaction of DCs with LIGHT- or LTαβ-expressing cells (such as B cells and T cells, or even lymphoid-tissue inducer cells in the gut) promotes DC proliferation under inflammatory conditions. Given the importance of DCs for generating an effective immune response, such redundancy in the source of ligands for LTβR would make sense.
Interestingly, a more careful examination of the CD11b+ DC population revealed a subpopulation of CD11b+ DCs that expresses high levels of endothelial cell-selective adhesion molecule (ESAM)31. These DCs, which turn over very rapidly, were selectively lost when either Notch or LTβR signalling was specifically ablated in DCs. Thus, it appears that this subset of rapidly proliferating CD11b+ DCs is specifically maintained by LTβR and Notch signalling. It is unclear whether the LTβR and Notch pathways collaborate to maintain the survival of this CD11b+ DC subset, or whether a more complicated form of crosstalk occurs between these pathways.
There is some information on the signals that negatively regulate DC survival. Ware and colleagues have shown that mice deficient in BTLA (B and T lymphocyte attenuator) or the TNF superfamily receptor HVEM (herpesvirus entry mediator) have increased numbers of CD8α− splenic DCs compared with control mice, suggesting that the stimulation of BTLA through interaction with HVEM negatively regulates this DC subset. This was a satisfying finding because LIGHT can bind to HVEM, suggesting that BTLA–HVEM interactions serve as the negative counterpoint to LTβR signalling. Interestingly, the administration of agonistic LTβR-specific antibodies can increase DC numbers in mice, suggesting that the LTβR pathway can 'override' BTLA-mediated negative regulation of DC proliferation32. This may be important during inflammation, when the expression of LTαβ is induced in T cells33.
In summary, TNF superfamily members have crucial roles in shaping the priming environment of the lymphoid tissue, both in the steady state and in the context of inflammation. Without these TNF superfamily receptor-dependent events, T cell–DC crosstalk would occur very inefficiently.
The TNF superfamily and the reactive lymph node
T cell priming with exogenous antigens takes place in the highly organized structures of secondary lymphoid organs and, as discussed, TNF superfamily members are important for setting up these environments. However, TNF superfamily members also have an active role in shaping the T cell response by facilitating crosstalk between T cells and DCs during T cell priming. The effects of TNF superfamily receptors are bidirectional. Some TNF superfamily receptors transmit T cell-delivered signals into DCs and promote the upregulation of cytokines and co-stimulatory molecules in a process known as DC licensing. Other TNF superfamily receptors are upregulated by activated T cells, and these T cell-intrinsic signals shape and polarize the ensuing T cell response. A complex integration of various TNF superfamily receptor-mediated signals is crucial for optimizing T cell responses (Fig. 1). In this section, we focus on those TNF superfamily receptors that are triggered specifically during T cell–DC crosstalk and their impact on the T cell response.
Inducible co-stimulatory TNF superfamily receptors. Given that TNF superfamily members are often upregulated by antigen-activated lymphocytes during priming, it is not surprising that these molecules have an important role in T cell–DC interactions. The experimental systems used to determine the contribution of signalling mediated by different TNF superfamily members during T cell responses are quite diverse and can often lead to different results. This is probably due to the relative levels of antigen and/or the extent of inflammation in each setting (Table 3). TNF superfamily members that co-stimulate a T cell response are defined here as mediators of T cell-intrinsic signals that augment T cell activation during T cell receptor (TCR) ligation. As the expression of these TNF superfamily receptors on T cells is induced following antigen-mediated activation, these receptors are termed inducible co-stimulatory TNF superfamily receptors.
Inducible co-stimulatory TNF superfamily receptors can make distinct and complimentary contributions to the shaping of an effective T cell response, with some being required for optimal priming and others for memory T cell formation and/or maintenance. A common theme for such interactions is that expression of the cognate TNF superfamily ligand on DCs often requires pre-stimulation of the DCs through CD40 or through pattern-recognition receptors (PRRs), suggesting that the expression of these TNF superfamily ligands requires regulation via a priori activation signals in DCs (Fig. 1). This makes sense given that many of these ligands have been implicated in tissue pathology during autoimmune and allergic responses. We have focused here on co-stimulatory TNF superfamily receptors that are activated by membrane-bound ligands displayed by DCs (for brevity, we have omitted some TNF superfamily receptor–ligand interactions that occur between other immune cells, such as B cell–T cell interactions). Listed in Table 3 are examples of T cell-expressed co-stimulatory TNF superfamily receptors — namely, OX40, 4-1BB, CD27 and GITR (glucocorticoid-induced TNFR-related protein). When engaged by their ligands expressed by activated DCs, these receptors can shift the balance between robust immunity and an abortive or even a tolerogenic immune response to antigens.
The TNF superfamily and DC licensing. DC licensing is a process that occurs early in an immune response and is achieved through cognate interactions between antigen-specific CD4+ T cells and antigen-bearing DCs (Fig. 1). DC licensing can be supported by various signals derived from T helper (TH) cells, such as interferon-γ (IFNγ). TNF superfamily ligands expressed by antigen-specific CD4+ T cells can also influence the phenotype and the function of antigen-bearing DCs, thereby licensing DCs to cross-prime CD8+ T cell responses. For example, these ligands can alter the expression of MHC molecules and co-stimulatory molecules (such as CD80 and CD86) and the production of cytokines such as interleukin-12 (IL-12) by DCs. CD40L and LTαβ are both upregulated on antigen-specific CD4+ T cells within 24 hours of infection or immunization33, and these TNF superfamily ligands can 'license' DCs by signalling through CD40, which is upregulated on activated DCs, and through LTβR, which is constitutively expressed on DCs. In the context of immunization, these two pathways are not always mutually compensatory during immunization regimes that do not promote substantial inflammation (that is, regimes involving cell-associated or protein antigens that are processed by DCs in the absence of adjuvant, or involving antigens that are not derived from replicating pathogens). In this section, we compare the effects of CD40 versus LTβR signalling in DCs to gain clues as to why more than one TNF superfamily member may be required for DC licensing.
Mechanism for CD40-mediated licensing. CD40 has a very important role in licensing DCs to prime CD8+ T cell responses. Blocking CD40-mediated signalling impairs both primary and memory T cell responses against a broad range of immunogens34. Moreover, CD40 ligation can render an otherwise tolerogenic response immunogenic35. Expression of CD40 on DCs is crucial for cytotoxic T lymphocyte (CTL) function36 and for CD8+ T cell memory37, and the ligation of CD40 on DCs results in the upregulation of co-stimulatory molecules (including CD80, CD86 and CD70) as well as of other TNF superfamily members, such as 4-1BBL, OX40 ligand (OX40L) and GITR ligand (GITRL). The upregulation of CD70 expression by DCs is a crucial component of CD40-mediated DC licensing, as CD70 blockade abrogates the pro-inflammatory effects of CD40 stimulation in vivo38. CD40 also induces the expression of pro-inflammatory cytokines, such as IL-1β, IL-6 and IL-12, by DCs. Of these cytokines, IL-12 is most restricted to licensed DCs and is clearly important for CD8+ T cell responses, as defective or absent IL-12 signalling impairs CD8+ T cell clonal expansion, function and memory39.
Mechanism for LTβR-mediated licensing. T cell help is not mediated exclusively through CD40. The discovery of a help-dependent CD8+ T cell response that is independent of CD40 and CD40L40 supports the existence of additional licensing pathways. An absence of LTβR signalling during T cell–DC interactions renders DCs functionally defective ex vivo33, suppresses CD8+ T cell-mediated graft rejection41, protects the host from CD8+ T cell-driven systemic shock following LCMV infection42 and impairs antiviral CTL responses43,44. Our laboratory has examined how DC-intrinsic LTβR-dependent signalling may modulate CD8+ T cell responses in vitro and in vivo. Although IL-12 expression was not readily induced by LTβR signalling in vitro, we found that LTβR signalling (either alone or in synergy with lipopolysaccharide) induces the production of IFNα and IFNβ by DCs36. This is consistent with the finding that LTβR drives type I IFN expression in stromal cells in response to viral infection45,46. Although LTβR-deficient DCs have defects in their ability to prime CD8+ T cell responses, our studies found that exogenous IFNα could rescue normal CD8+ T cell population expansion in vitro36. This suggests that LTβR-induced production of IFNα and IFNβ by DCs is an important requirement for CD8+ T cell priming in certain settings. IFNα/β receptor (IFNAR) signalling has been shown to be involved in priming antiviral CD8+ T cell responses, in particular by promoting the expansion of antigen-specific CD8+ T cell populations47. Although CD8+ T cell-intrinsic IFNAR signalling has been implicated in this process47,48, type I IFNs produced by DCs downstream of LTβR signalling may also function in an autocrine manner, as IFNAR-deficient DCs may have a defective stimulatory function49. Therefore, it is reasonable to conclude that an important outcome of LTβR signalling in DCs is the induction of type I IFN production for optimal CD8+ T cell priming.
Are CD40 and LTβR signals in DCs redundant or cooperative? TH cell-expressed LTαβ and CD40L are both required to license DCs for CTL priming. Therefore, the CD40 and LTβR signalling pathways are likely to collaborate to promote DC maturation. Among other effects, CD40 and LTβR induce, respectively, the expression of IL-12 and the expression of type I IFNs. These cytokines have been implicated in priming CD8+ T cell responses and in programming functional CD8+ T cell memory. IL-12- or IFNα-mediated signalling in antigen-activated CD8+ T cells was shown to induce chromatin remodelling that favours the acquisition of CD8+ T cell effector and memory functions, possibly providing an explanation for how qualitative differences in T cell priming produce lasting effects in memory cells106. It is unclear how CD40-induced IL-12 and LTβR-induced type I IFNs can distinctly and complementarily programme short- and long-term gene expression in CD8+ T cells, and many questions concerning CD40- and LTβR-mediated DC licensing remain. The ligands for these receptors are upregulated in concert, and both CD40 and LTβR share many of the same signalling pathways, with some exceptions (Box 2); thus, the unique signals that induce IL-12 versus IFNα and IFNβ production remain to be determined. Furthermore, it is unclear which aspects of the CD8+ T cell response depend on the production of IL-12 and type I IFNs by DCs, and which aspects require LTβR- and CD40-induced expression of other soluble or cell-bound immune mediators.
The TNF superfamily in peripheral inflammation
As reviewed above, the activation of TNF superfamily receptors can directly co-stimulate T cell responses and can licence DCs so that they become more immunostimulatory. The contributions of both T cell-associated and DC-associated TNF superfamily receptors shape the nature of the T cell response to foreign and self antigens in the periphery, thereby tipping the balance towards immunity rather than tolerance. DCs in mucosal tissues are distinct from other DC populations and have the challenging task of maintaining tolerance to a large variety of normally harmless antigens, including antigens from host-resident commensal microorganisms, innocuous inhaled protein antigens and ingested food antigens (Table 2). As exciting new data implicate TNF superfamily members in the regulation of immune responses in mucosal environments, we focus here on TNF superfamily receptors in the gut and in the airways. An important role for TNF superfamily receptors in other, non-mucosal, peripheral organs50 and in the skin51 is also emerging, but a discussion of these roles is beyond the scope of this Review.
The TNF superfamily and intestinal inflammation. The maintenance of tolerance in mucosal tissues is complicated by an ever-present and diverse host-resident microbial community. At such sites, DCs must maintain ongoing tolerance to prevent inflammation and tissue damage. This is a delicate balance, and the nature and maturation status of the DCs in these locations are an important key to understanding how tolerance to the microbiota is maintained. Indeed, it is in these locations that the activation of TNF superfamily receptors on DCs may profoundly affect immune homeostasis.
Our knowledge of how the TNF superfamily affects the homing, homeostasis and function of lamina propria-resident DCs is limited, but some key concepts are emerging (Fig. 2). Recent work by Fu and colleagues has revealed a DC-intrinsic role for LTβR signalling in orchestrating immunity to Citrobacter rodentium infection. However, unlike the classical T cell–DC crosstalk described for the LT system in peripheral lymphoid organs33,36, DCs in the gut interact with innate lymphoid cells in colonic lymphoid follicles52. Therefore, expression of LTαβ on innate lymphoid cells is important not only for orchestrating the formation of innate lymphoid follicles and colonic lymphoid follicles (via crosstalk with stromal cells expressing LTβR)53, but also for 'conditioning' LTβR-expressing DCs in the gut. In the gut environment, LTβR signalling appears to be essential for the production of IL-23, which in turn provokes the production of IL-22 by innate lymphoid cells54. These studies provide a putative mechanism for the C. rodentium-induced colitis that is attenuated in LT-deficient mice55, and perhaps for other models of colitis in which LT inhibition has been beneficial56. Interestingly, a similar paradigm has been reported in colitis triggered by CD40 ligation. Powrie and colleagues showed that agonistic CD40-specific antibodies could induce colitis in the absence of T cells, and the CD40-specific treatment induced IL-23 production by DCs57. In the absence of T cells, the authors showed that IL-17 was produced in the colitic gut tissue, and it is tempting to speculate that similar crosstalk occurs between CD40-expressing DCs and CD40L-expressing innate lymphoid cells. Nevertheless, the link to IL-23 in these studies provides an explanation for the efficacy of CD40L-specific blocking antibodies in the treatment of colitis in mouse models58,59.
Interestingly, other TNF superfamily receptors appear to have an anti-inflammatory role in the gut. In particular, HVEM–BTLA signalling attenuates intestinal inflammation60, suggesting a possible counterpoint to the LTβR pathway in the regulation of mucosal DCs. This is not unlike the negative regulatory role described for HVEM–BTLA signalling in curtailing DC survival in the periphery32. Furthermore, RANK signalling in gut-associated DCs appears to provoke IL-10 secretion, and the administration of RANKL promotes oral tolerance61. The anti-inflammatory effects of RANK stimulation in DCs are associated with increased numbers of regulatory T (TReg) cells in the gut, and the anti-inflammatory function of TReg cells during colitis is abrogated by RANK blockade62. Thus, the integration of TNF superfamily receptor signals in DCs may dictate the delicate balance between tolerance and immunity in the complex environment of the gut. How such signals are affected by the composition of the local microbiota, and vice versa, remains unexplored.
The TNF superfamily and airway inflammation. Although it is clear that TNF superfamily members are important for the clearance of lung-resident pathogens (Table 3), a role for TNF superfamily receptors in chronic inflammation in the lungs is emerging. Not unlike the gut mucosal tissue, the lungs are a site where coordinate interactions can occur between infiltrating leukocytes, airway-resident DCs (see Table 2) and the epithelial cells of the tissue itself. For example, OX40–OX40L interactions can drive inflammation and promote eosinophilia in the lungs following exposure to allergens, and OX40 signalling in memory CD4+ T cells appears to be important for the recall response of these cells to antigens in the lungs63. However, signalling by OX40 in airway epithelial cells was also shown to be important for the production of thymic stromal lymphopoietin (TSLP), which drives an inflammatory TH2-type immune response in the lungs51. This could feasibly fuel a 'vicious circle' involving the repeated priming of memory TH2 cells by allergen-presenting OX40L+ lung DCs, and the continual polarization to a TH2 phenotype because of crosstalk with lung epithelial cells. However, it is important to keep in mind that during chronic allergen exposure, lung remodelling is also quite deleterious to the host, and the notion that TNF superfamily receptors simply control pro-inflammatory T cell responses in the context of mucosal tissues is likely to be over-simplistic. For example, during chronic allergen exposure (such as that induced in the chronic house dust mite model), tissue fibrosis and lung remodelling are driven by LIGHT–LTβR and LIGHT–HVEM interactions, and the deleterious effect of LTβR signalling in the lungs was associated with the production of transforming growth factor-β (TGFβ), an important pro-fibrotic mediator64. Thus, a complex interplay between leukocytes and the lung microenvironment is important for the polarization of allergic responses as well as for the subsequent fibrotic response that impairs lung function.
Chronic inflammation in the lungs can also induce the formation of ectopic lymphoid structures known as inducible bronchus-associated lymphoid tissue (iBALT). These structures, which are observed in chronic obstructive pulmonary disease (COPD) as well as during and after influenza virus infection, support local immune responses such as plasma cell generation. Although lymphoid-tissue inducer-like cells are important for the formation of isolated lymphoid follicles in the gut, other types of cells can initiate iBALT formation in the airways. DCs have been shown to be important for iBALT formation and maintenance65, and, interestingly, these DCs were an important source of LTαβ, a result echoed by the more recent finding that LTαβ expression by DCs is required for HEV maturation9. Whether LTαβ on DCs stimulates DC-expressed LTβR in an autocrine manner remains unclear; however, it is likely that this reservoir of LTαβ does communicate with the underlying stroma to induce the production of lymphocyte-attracting chemokines (such as CXCL13) that serve to recruit other leukocytes into the iBALT. More recently, TH17 cells were also shown to be important in the formation of iBALT, whereas LTαβ–LTβR interactions were needed to sustain these structures66. Thus, not unlike the scenario of chronic allergen exposure, during which TNF superfamily interactions between leukocytes and the lung microenvironment are important for lung remodelling, the orchestration of iBALT formation may also rely on cognate interactions between multiple cell types, including DCs, stromal cells and iBALT-infiltrating lymphocytes. As iBALT formation could contribute to pathogen clearance, further study of how TNF superfamily members affect these cellular interactions may inform vaccine design.
The TNF superfamily in human disease
The first therapeutics to target the TNF superfamily were drugs that neutralize the activity of TNF. These drugs are particularly useful for the treatment of inflammatory bowel disease (IBD) and rheumatoid arthritis, and this makes sense because TNF has pleiotropic effects on the inflammatory cascade, including (but not limited to) neutrophil recruitment67. Although TNF blockers have had a tremendous impact on these chronic diseases, other TNF superfamily members clearly have an important role in the aetiology of autoimmune diseases. Despite this, there are only two other TNF superfamily pathways targeted by approved therapeutics (see Table 1 for current TNF superfamily-directed therapies that have been approved by the US Food and Drug Administration, that are in clinical trials or that have been proved efficacious in preclinical animal models). Although TNF blockers have potent anti-inflammatory properties, many of the pathways listed in Table 1 also have an important role in DC biology. As attenuating DC function can either prevent further T cell activation or induce tolerance, DC-directed therapies may have a profound impact on a wide variety of diseases, including multiple sclerosis, graft-versus-host disease, diabetes and IBD. As such, when aberrant DC activity is at the heart of disease aetiology, these therapies merit consideration. In this section, we focus on the promise of targeting TNF superfamily members for the eradication of cancers, and we explore the unmined potential of targeting TNF superfamily receptor-mediated DC licensing as a means to reprogramme immunogenic DCs so that they acquire tolerogenic (or non-stimulatory) properties.
TNF superfamily receptor co-stimulation and tumour immunity. As the expression of TNF superfamily ligands by DCs is generally induced by PRR stimulation, these molecules may be limiting during immune responses that do not provoke substantial inflammation. Immune responses to tumours can often be augmented by the administration of agonist antibodies specific for TNF superfamily receptors. However, agonist antibody therapies can have risks for the host68. Enforced expression of TNF superfamily ligands by DCs, which are the natural cellular source of these molecules, can augment the tumoricidal activity of T cells in a more defined manner. Such experiments have revealed that T cell–DC interactions via TNF superfamily members are normally limiting but have significant potential for promoting tumour clearance. Just as these pathways have a diverse role in shaping the T cell response to foreign antigens, the activation of distinct TNF superfamily receptors on T cells can have unique effects on the nature of the T cell response to tumours. For example, the enforced expression of TNF superfamily ligands by DCs can break tolerance to tumours (in the case of CD70)69, relieve suppression by TReg cells (in the case of OX40L)70, provide direct co-stimulation to tumour-specific T cells (in the case of GITRL or OX40L)71,72, polarize TH cells towards a TH1 phenotype (in the case of OX40L)73 and enhance antitumour memory T cell responses (in the case of 4-1BBL)74. Given the diverse functions of these TNF superfamily receptors in eliciting antitumour responses, combinatorial therapies in which multiple TNF superfamily ligands are delivered to DCs may make sense.
Therapeutic manipulation of TNF superfamily receptor-dependent DC licensing. DCs are crucial drivers of T cell-mediated autoimmune disease in rodent models, and TNF superfamily receptors that are involved in promoting DC maturation have been implicated in pathological inflammation. Inhibition of CD40 signalling with a blocking antibody specific for CD40L protects from disease in animals models of multiple sclerosis, type 1 diabetes, collagen-induced arthritis and colitis. Inhibition of LTβR signalling also protects from these T cell-driven diseases, although, similarly to the effects of CD40 signalling inhibition, protection usually involves reduced severity or delayed progression of the disease rather than full tolerance induction. Blocking CD40 or LTβR signalling can prolong allograft survival, but lasting tolerance is only achieved by combination therapies that couple CD40 or LTβR signalling inhibition with co-stimulatory molecule blockade or immunosuppressants. Importantly, dual inhibition of CD40 and LTβR signalling can also result in allospecific tolerance induction107 and may provide a means of altering DC licensing by promoting the apoptosis of alloreactive T cells and/or by encouraging the differentiation of TReg cells. These strategies may be the key to establishing long-lasting tolerance without the undesirable effects of long-term treatment with broad-acting immunosuppressants.
Conclusion and perspectives
Even before an immune response occurs, TNF superfamily members exert influence on lymphoid tissues in a way that maximizes T cell–DC encounters and also promote the homeostasis of the DCs themselves. One can therefore imagine that, within ectopic tertiary lymphoid structures, the blockade of TNF superfamily signals may compromise pathogen clearance (as in the case of iBALT structures) or may attenuate chronic inflammation (as in the case of ectopic tertiary lymphoid structures found at sites of autoimmune attack). This could be quite relevant for diseases such as secondary progressive multiple sclerosis, in which immunomodulation in the peripheral compartment appears to have no clinical benefit. Beyond these homeostatic functions, however, TNF superfamily receptor-orchestrated crosstalk between T cells and DCs can lead to enhanced T cell proliferation, cytokine secretion and memory T cell maintenance in the context of an immune response. In the periphery, amplifying TNF superfamily receptor signals can potentially break tolerance to tumours or to self antigens. In the mucosal tissues, where DCs must constantly process harmless antigens and maintain tolerance, the dysregulation of TNF superfamily receptor activation and/or expression may have dire consequences. Taking into consideration the complimentary functions of TNF superfamily members in T cell–DC crosstalk, one can imagine selecting combinations of TNF superfamily receptor-targeted therapies to handle distinct disease aetiologies. Thus, there exists considerable untapped potential in targeting TNF superfamily members, either alone or in combination, for the treatment of significant health problems that exert a tremendous burden on individuals, their families and society.
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Funding for the research on how the lymphotoxin pathway supports T cell–DC crosstalk was provided by the Canadian Institutes of Health Research (MOP 67157). The authors wish to acknowledge D. Ng, L. Snell and O. Rojas for critical reading of the manuscript.
The authors declare no competing financial interests.
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- Dendritic cell
(DC). A potent antigen-presenting cell that acts as a sentinel of the immune system. Located throughout peripheral tissues as well as in the lymphoid tissues of the periphery and the mucosae, these cells acquire and process antigens and present them to rare, antigen-specific T cells.
- TNF superfamily receptors
A molecular superfamily of receptors that trigger signalling events in a wide range of cell types, including cells of the immune system, such as T cells and DCs. Some TNF superfamily receptors (such as TNFR1) can activate cell death (in addition to other functions), whereas others (such as LTβR) can promote cell survival and inflammation.
- Secondary lymphoid organs
Highly organized anatomical structures, including the spleen and peripheral lymph nodes as well as the Peyer's patches and mucosa-associated lymphoid tissues (such as isolated lymphoid follicles and nasopharynx-associated lymphoid tissue). The cellular compartmentalization within these structures is actively maintained by constitutive LTβR signalling.
- Lymphoid-tissue inducer cells
A population of cells 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, and this function is mediated by their interactions with lymphoid-tissue organizer cells.
- Subcapsular sinus macrophages
Specialized macrophages that reside in the subcapsular sinuses of lymph nodes and are efficient at capturing antigens from the lymph.
- Microfold cells
Specialized antigen-sampling cells that are located in the follicle-associated epithelium of the organized mucosa-associated lymphoid tissues. Microfold cells deliver antigens by transepithelial vesicular transport from the aerodigestive lumen directly to subepithelial lymphoid tissues of the nasopharynx-associated lymphoid tissue and Peyer's patches.
- Tertiary lymphoid structures
(Also known as follicle-like structures). Collections of lymphocytes that occur in the context of pathogen-driven or autoimmune inflammation. The organization of such structures varies: some are clusters of lymphocytes and DCs, whereas others have ongoing germinal centre reactions. The organization of such structures is maintained by constitutive LTβR signalling, although the cellular source of LTαβ can vary.
- DC licensing
A concept that a DC must be converted to a functional state by an antigen-specific T helper cell in order to activate cytotoxic CD8+ T cells. T helper cells license DCs by expressing co-stimulatory molecules (such as the TNF superfamily ligands CD40L and LTαβ) or producing cytokines (such as IFNγ).
- Inducible co-stimulatory TNF superfamily receptors
Co-stimulation of the T cell response involves the integration of many signals, including those induced by the engagement of CD28 and other T cell-associated TNF superfamily receptors. T cell-expressed TNF superfamily receptors are typically upregulated in response to T cell receptor activation (hence the term 'inducible co-stimulators'). Likewise, the ligands for these inducible co-stimulators are TNF superfamily members, many of which are upregulated by activated DCs.
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deLuca, L., Gommerman, J. Fine-tuning of dendritic cell biology by the TNF superfamily. Nat Rev Immunol 12, 339–351 (2012). https://doi.org/10.1038/nri3193
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