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Keywords:

  • Autoimmunity;
  • Hallmark cytokines;
  • IL-23;
  • Polarization

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References

During the past decade, it has been firmly established that IL-23 is essential for disease development in several models of autoimmune disease, including psoriatic skin inflammation, inflammatory bowel disease (IBD), and experimental autoimmune encephalomyelitis (EAE). The mechanism by which IL-23 exerts its pathogenic role has been mostly scrutinized in the context of Th17 cells, which were thought to mediate autoimmunity by secretion of IL-17 family cytokines. However, the picture emerging now is one of multiple IL-23-responsive cell types, pro-inflammatory cytokine induction, and pathogenic “licensing” following an IL-23-dominated interaction between the T cell and the antigen-presenting cell (APC). This review will focus on our changing view of IL-23-dependent autoimmune pathologies with a particular emphasis on the responder cells and their IL-23-induced factors that ultimately mediate tissue destruction.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References

Regardless of the underlying mechanism by which autoimmunity is initiated, the inevitable outcome is a chronic immune response against self-antigen accompanied by the accumulation of inflammatory mediators. Extensive pathology in the affected organs is characteristic of late-stage autoimmunity and this devastating process is often well underway when a disease is diagnosed. It is this stage of autoimmunity that is most relevant when considering therapeutic intervention, as patients are rarely aware, prior to health complaints, that an autoimmune manifestation will ultimately take place.

We are now in possession of substantial evidence that implicates pro-inflammatory cytokines in a wide range of auto-immune pathologies. The early success of anti-TNF-α therapy in rheumatoid arthritis galvanized the notion that a number of other autoimmune diseases, in which similar mechanisms may operate, could also be treated by blockade of the cytokines thought to be responsible for pathogenesis [1]. These pro-inflammatory cytokines are produced by CD4+ T helper cells, which orchestrate immune responses by sending out secreted signals to other immune cells and stromal cells. Not only the cytokines expressed, but the mechanisms controlling the generation of the cytokine-secreting cells themselves have been heavily scrutinized, with the long-term goal being to treat autoimmune disease by neutralizing the effector cytokines secreted by autoaggressive T cells. We now know that the differentiation of effector T cells is in itself dependent on cytokines present at the time of their activation. The subsequent polarization, which takes place when T-cell receptor, costimulatory, and cytokine signals combine (reviewed in [2]), can result in a broad range of biological functions within the activated T cells. When we consider the sheer number of cytokine combinations theoretically available to a T cell, it is perhaps surprising that so few cellular “phenotypes” have been characterized.

Immunologists appear to be keen on categorizing different subsets of T cells, with a rather rigid attribution of biological function being applied to each subset. One could argue that this trend began some 40 years ago, when T cells were subdivided into CD4+ helpers and CD8+ cytotoxic killers. Twenty years later, the CD4+ helper cells were again separated into Th1 and Th2 cells, and the “hallmark” cytokines they secreted were used as their form of irreversible identity (reviewed in [3]). With the benefit of hindsight, this straightforward categorization has proven to be exceedingly simple and a far more complex paradigm characterized by flexibility and “plasticity” is now emerging in its place (reviewed in [4]).

Poles apart: Antigen-presenting cells dictate the differences

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References

At the initiation of an immune response, professional antigen-presenting cells (APCs) preside over the decision between attack and defense and represent an important checkpoint in the transition from innate to adaptive immunity. Dendritic cells (DCs) and macrophages express an array of molecules designed to sense infection and cellular distress, thus constantly interpreting a vast variety of environmental stimuli, which are often encountered simultaneously with foreign and self-derived antigens.

During bacterial infections, DC activation proceeds via binding of microbial components to Toll-like receptors (TLRs) [5, 6], followed by the release of pro-inflammatory cytokines and the presentation of bacteria-derived peptides, which are recognized by T cells. In the case of autoimmunity, the necessary triggers remain elusive. Several ideas concerning these autoimmune triggers have been formulated, including viral infections (reviewed in [7]), degenerative processes, and sensing of so-called danger signals [8]. One tangible example of the latter is the excessive release of uric acid from dying cells [9], but additional stress signals such as alarmins are being identified (reviewed in [10]).

Among the most studied APC-derived pro-inflammatory cytokines are IL-12 and IL-23. These are heterodimeric molecules sharing a profound structural similarity in which a common subunit, p40, is required for their function and receptor binding. IL-12 is comprised of p40 covalently linked to the p35 subunit [11], while IL-23 consists of the same p40 subunit linked to a unique p19 subunit [12]. All of these subunits are predominantly expressed by activated DCs in vivo, but the tight regulation of p35 and p19 expression dictates whether an activated DC or macrophage will secrete bioactive IL-12 or IL-23 [12, 13].

The most heralded function of IL-12 is to induce the transcription factor T-bet and direct the differentiation of naïve T cells into IFN-γ-producing Th1 cells [14-17]. The apparent need for IFN-γ in Th1 development was shown to be due to its role in perpetuating IL-12Rβ2 expression on differentiating Th1 cells [18]. IL-18 also augments IFN-γ expression in Th1 cells by inducing IL-12Rβ2 expression, but is itself not sufficient for Th1 differentiation [19, 20]. In fact, expression of IL-18R is likely dependent on IL-12 signaling, placing IL-18 downstream of IL-12 signaling in the Th1 differentiation cascade [21]. However, the role of IL-18 signaling extends to APCs themselves, as mice lacking IL-18Rα show a reduced ability to secrete IL-12p40 [22].

The ability of IL-12 to initiate the polarization of Th1 cells dominated our perception of how pathogenic autoimmune T cells can emerge for many years (see the timeline in Fig. 1). The use of IL-12p40-deficient mice or neutralizing Abs against IL-12p40 was among the most powerful interventions to prevent experimental autoimmunity [23]. The discovery of IL-23 and its use of the p40 subunit opened up the possibility that attributing auto-inflammatory disease initiation to IL-12 and Th1 cells may have been based on mistaken identity. Shortly after the discovery of IL-23, it was shown that mice lacking IL-12 (p35) were highly susceptible to experimental autoimmune encephalomyelitis (EAE), whereas IL-12/23p40-deficient mice were indeed completely resistant [24]. This observation caused a paradigm shift, and the fundamental role of IL-23 rather than IL-12 as a master regulator in autoimmune disease was confirmed when mice lacking the unique IL23p19 subunit were found to phenocopy IL-12/23p40−/− mice [25]. Contrary to IL-12, IL-23 does not induce the differentiation of IFN-γ-producing Th1 cells, but drives the expansion of a highly encephalitogenic, IL-17-producing T-cell population [26]. This was among the most exciting among a fine selection of observations made in the long history of studying the functions of IL-12 and IL-23 (Fig. 1), and has in itself spawned a new field of research dedicated to unraveling the regulation and function of IL-17-producing helper T cells, so called “Th17” cells.

image

Figure 1. Key events in the discovery of IL-12 and IL-23. During the two decades since the discovery of IL-12, the prevailing paradigms in autoimmune pathology have significantly changed. Initially, IL-12 activated Th1 cells were considered to be the pathogenic cell population, followed by a paradigm shift to IL-23 driven Th17 cells. During more recent years, a new picture with multiple roles of IL-23 is emerging in its place.

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Sensing IL-23: Permission to be pathogenic

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References

While IL-12 can be sensed by naïve cells, the complete IL-23 receptor is not expressed on their surfaces. Thus, the factors equipping T cells with the ability to sense IL-23 became a major focus of research (reviewed in [27]). Much like the cytokines of the IL-12 family, the corresponding IL-23 receptors also share subunits that are required for the signaling of multiple cytokines. The IL-23 receptor is composed of a common subunit, IL-12Rβ1, and a second protein unique to IL-23 signaling, IL-23Rα [28]. IL-12Rβ1 is also required for IL-12 signaling, but to date the only known function of the IL-23Rα chain is to transmit the signals of IL-23. Therefore, T cells lacking IL-12Rβ1 cannot respond to IL-12 nor IL-23. T cells lacking IL-23Rα cannot respond to IL-23, but retain IL-12 signaling capability. In the context of the widely used animal model for multiple sclerosis, EAE, deficiency of IL-12Rβ1 completely abrogates disease induction [29]. The observation that IL-12Rβ2-deficient mice are fully susceptible to EAE confirms that IL-12 signaling is dispensable for EAE induction, and the missing signals from IL-23 are responsible for the resistance seen in IL-12Rβ1 knockouts [30]. IL-23 was soon after definitively confirmed as the major pathogenic molecule in EAE, due to a requirement for IL-23 signals to drive proliferation, expansion, and survival of pathogenic T cells in the CNS [25, 31]. The absence of the unique IL-23Rα chain also confers complete resistance to actively induce EAE [32], and it has been suggested that, in the context of neuroinflammation, IL-23 signaling on antigen-specific αβ T cells is sufficient to cause disease.

The importance of IL-23 in the development of numerous autoimmune diseases (summarized in Fig. 2) has by now been established, but the fact that naïve T cells do not express il23r raises questions about the upstream signaling events that render T cells sensitive to IL-23 at later stages. This mechanism of action is similar to IL-18, which also does not act on naïve T cells lacking the necessary receptors to sense its presence [28, 32]. It seems that IL-23R expression on T cells is induced first after activation in the presence of IL-21 [33, 34], a STAT3-dependent cytokine. IL-21 is abundantly expressed by T cells activated in the presence of IL-6 [35, 36], which is likely provided by activated dendritic cells and macrophages in vivo. As such, the signals provided by APC-derived IL-6 are crucial at the moment of T-cell activation, conferring responsiveness to IL-23. One could reason that mice lacking IL-21 or its receptor may well phenocopy p19−/− mice if IL-21 was essential for IL-23R expression. Interestingly, IL-21 signaling is not required for EAE induction [37], but IL-23 is an absolute necessity [25]. These findings collectively imply that IL-21-independent mechanisms of IL-23R expression exist in vivo. However, sustained IL-23 signaling on T cells seems to be of importance for maintaining inflammation. For example, during the recovery phase of EAE, reduced levels of IL-23 expression were observed in draining lymph node-derived DCs [38]. This reduction also mirrored a drop in T-cell-derived IL-17, which points to a correlation between the cessation of IL-23 expression and recovery from disease associated with reduced pathogenic T-cell generation and/or activity.

image

Figure 2. Divergent but overlapping functions of IL-23 in different models of autoimmunity. IL-23 has been shown to be an essential messenger in different models of autoimmunity, including experimental autoimmune encephalomyelitis (EAE), inflammatory bowel disease (IBD), and psoriatic skin inflammation. Importantly, IL-23 not only acts on conventional αβ T cells, but also on innate cells such as γδ T cells and ILCs, with partially similar effects on all three cell types, for example induction of IL-17 secretion and stabilization of RORγt expression. However, while the involvement of any of these cell types in the outlined autoimmune diseases has been clearly demonstrated in animal models, the relative contribution to disease progression in humans remains to be determined.

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IL-23 as a therapeutic intervention point

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References

Blockade of IL-23 in the clinical setting is now receiving substantial attention after the rapid accumulation of studies highlighting the essential role of IL-23 in so many animal models of inflammation. The connection between IL-23 and autoimmune disease in humans is supported by evidence showing that polymorphisms in the il23r locus are linked to Crohn's disease and psoriasis (reviewed in [39]). Interestingly, a recent gene association study looking at multiple sclerosis highlighted a number of immune related genes for this disease, but not IL-23 nor IL-23R [40].

A major advantage of IL-23 as a therapeutic target is that it appears to be effectively inhibited in vivo by monoclonal antibodies and some pharmacological inhibitors of IL-12/23 subunit expression. Ustekinumab is a human monoclonal IgG1 antibody, which binds the p40 subunit and prevents functional IL-12 and/or IL-23 from interacting with IL-12Rβ1. This inhibitory activity blocks downstream events of both the IL-12 and IL-23 signaling cascade [41]. Two recent clinical trials showed that patients with severe psoriasis benefited significantly from a treatment course with ustekinumab, according to the psoriasis area and severity index (PASI) criteria [42, 43]. In fact, anti-p40 treatment was even more effective than neutralization of TNF-α using Etanercept in the treatment of psoriasis [44]. The same antibody was unfortunately not efficacious in treating MS [45], perhaps due to the fact that IL-23 may be important prior to the appearance of clinical symptoms and not in subsequent disease stages when patients appear with MS-associated neurological impairments. Alternatively, it is possible that the neutralizing antibody will have limited access to the inflamed CNS where IL-23 has been shown to perpetuate the immune response [46]. Lastly, Ustekinumab also blocks IL-12, which has been proposed to have a regulatory function in autoimmunity [24, 25]. Hence, a more specific blockage of IL-23 without simultaneously neutralizing IL-12 might have been a more efficacious approach for the treatment of MS.

The rationale behind blockade of IL-23 in vivo stems from the idea that IL-23 is the major inducer of IL-17, a cytokine linked to many autoimmune diseases including multiple sclerosis and Crohn's disease [47-52]. However, the attempts to block IL-17A itself have shown limited efficacy in some systems, implying that inflammatory mediators other than IL-17 are important in these diseases. Some early experimental studies indicated that blockade of IL-17 may not be efficacious in human Crohn's disease patients, as neutralization of IL-17 was shown to exacerbate colitis in a mouse model [53]. Nonetheless, neutralization of IL-17A is now achievable in humans using Secukinumab (AIN457), and is shaping up after Phase II clinical trials to be a successful therapy in the pathogenesis of psoriasis, rheumatoid arthritis, and uveitis [54]. In fact, neutralization of IL-17A in human psoriasis patients was linked to a simultaneous downregulation of upstream signaling molecules important for IL-17A expression itself, including IL-12p40. Taken together, Th17 cells appear to be present in a number of autoimmune diseases, but their hallmark cytokine, IL-17, is not necessarily responsible for the symptoms associated with the diseases themselves.

All bark and no bite: Hallmark cytokines and misnomers

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References

The clear correlation between many autoimmune diseases and the presence of cytokine-expressing effector T cells at the sites of inflammation should allow us (in theory) to recognize the proteins secreted and make educated guesses at those proteins responsible for the tissue damage. However, a classical example of how this logic may fail is illustrated in the case of EAE, for which Th1 cells were thought to be ultimately responsible. Yet treating animals that had been immunized with the appropriate antigens to induce EAE with the hallmark Th1 cytokine IFN-γ surprisingly alleviated clinical disease. Conversely, blocking IFN-γ enhanced disease severity [55, 56]. Prior to this finding, administration of IFN-γ had been tested as a potential treatment for MS in the clinic. Deleterious effects had been reported in patients receiving this cytokine, and IFN-γ was subsequently deemed an unsuitable treatment for MS [57]. This valuable experience illustrates that it is not wise to immediately connect cytokine presence with cytokine pathogenicity, and further highlights the potential differences between MS and EAE in terms of pathological mechanisms. In fact, the final curtain is now lowering over the idea of a pathogenic role for Th1 cells in EAE, after the finding that T-bet-deficient mice are likely resistant to EAE, not due to their lack of Th1 cells, but rather due to disrupted IL23R expression [58].

Such confusing observations surrounding the function of Th1 cells and the role of IFN-γ in autoimmune disease appeared to be partially explained after the discovery of the CD4+ “Th17” subset, defined by the expression of IL-17A, the prototype member of the IL-17A cytokine family [59]. Th17 cells were in fact shown to be largely heterogeneous in nature, capable of expressing IL-17F, IL-22, and IL-21 alongside IL-17A. The question was once again asked, as for Th1 cells some years before, whether or not the hallmark Th17 cytokine is a major player in disease pathogenesis. It appeared that a similar approach was being taken with respect to the simplicity of identification solely by IL-17A expression, although the community lacked the proper genetic tools to definitively show that CD4+ T-cell-derived IL-17A was crucial for Th17-mediated pathogenesis. At this point some caution had to be exercised, and the crucial distinction made between “pathogenic” and “IL-17A-expressing”. Another concept now becoming widely accepted is that IL-23 signaling by no means results in IL-17 expression alone. It seems to be impossible with current protocols to induce EAE or colitis in p40- or p19-deficient animals, which both lack functional IL-23 [25]. However, mice deficient in IL-17RA, IL-17A or both IL-17A and IL-17F show attenuated signs of EAE [60, 61], but develop disease nonetheless, which highlights a disconnection between IL-23 and IL-17. IL-17F deficiency in itself has no impact on the clinical course of EAE, and despite being an IL-23-induced cytokine, IL-17F is largely redundant in EAE pathogenesis [62]. Furthermore, a subset of CNS-invading Th17 cells known to produce IL-22 were also ruled out as potential mediators of disease [63]. In a model of chronic intestinal inflammation, IL-17A deficiency also does not ameliorate colonic inflammation after the transfer of IL-17A−/− naïve T cells to RAG-deficient host animals [64]. IL-17A was even shown to have a protective role in colitis by interfering with the function of pathogenic Th1 cells [65]. Furthermore, if the surplus or absence of IL-17A is modulated using diverse genetic or neutralization approaches, EAE disease can still persist [62, 66]. Collectively, it is clear that IL-23 controls important effector functions beyond the induction of IL-17 production by pathogenic T cells.

IL-17A, but no pathogenicity: The difference is in the differentiation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References

Although IL-23 was primarily identified as the initiating factor for IL-17A expression from T cells [26, 67], numerous studies have clearly shown that TGF-β and IL-6 are sufficient for Th17 differentiation in vitro and in vivo in the absence of IL-23 [68, 69]. A role for TGF-β in the generation of pathogenic Th17 cells in vivo has been suggested, given that local blockade of TGF-β at the time of immunization halts EAE progression [38]. However, long before the dawn of Th17 cells, TGF-β was lauded for its suppressive capabilities. Amelioration of inflammatory disease states including EAE and collagen-induced arthritis (CIA) were easily achieved after intravenous administration of TGF-β1 [70, 71]. Although it has been shown that Th17 cells can develop in the absence of TGF-β [72], numerous studies have shown a requirement for TGF-β [69, 73-75], Nonetheless, given the autoimmune complications associated with complete TGF-β deficiency, and the fact that TGF-β is produced by every cell in the body, there are no circumstances in which Th17 cells could arise in vivo in the complete absence of TGF-β. Therefore, the exact role of TGF-β is of importance, be that by providing a positive differentiation signal, or by suppressing other transcription factors such as T-bet and GATA-3, which would direct an activated T cell away from the Th17 lineage.

McGeachy et al. [70] convincingly demonstrated that Th17 cells can have different pathogenic capabilities depending on their route to IL-17 production. PLP-primed T cells were only encephalitogenic when exposed to IL-23 prior to transfer, whereas T cells polarized in the presence of TGF-β and IL-6 failed to induce disease when transferred directly into the cerebral ventricular space [73]. This approach also circumvented the potentially different migratory capabilities of polarized Th17 subsets by direct administration of the cells through the blood brain barrier [76]. Thus, despite IL-17A expression in both subsets, only T cells primed in the presence of IL-23 were “licensed to kill”. Why should IL-17A-expressing cells be so different in their capacity to induce disease? One answer could be that IL-17A is simply a “read-out” for T-cell activation in some circumstances, and the true culprit(s) behind Th17-associated pathogenesis are induced simultaneously with IL-17A by IL-23, but not by TGF-β and IL-6.

A keen observation was made in the study by McGeachy et al. [73] that a minority of the Th17 cells induced by TGF-β and IL-6 simultaneously expressed IL-10, and this was proposed to explain the lack of pathology observed after passive transfer of these cells [73]. IL-10 production may also explain why others have witnessed a reduced pathogenicity of Th17 cells induced by TGF-β and IL-6 [77]. Although IL-10 might indeed contribute to the reduced pathogenic potential of Th17 cells generated in this way, it is perhaps more likely that IL-23 induces another pathogenic cytokine and/or population of activated T cells. We and others were able to show that GM-CSF is in fact induced by IL-23, and that this cytokine is an absolute requirement for the encephalitogenicity of a T cell [78, 79]. Thus, a further axis exists at the core of Th17 cell biology, and is centered on how these “Th17” cells can also express GM-CSF.

With respect to multiple cytokine expression, an interesting facet of Th17 cells is their capability to produce cytokines with apparently opposing functions. Despite their obvious differences, a relationship between IFN-γ and IL-17A expression in T cells is clearly visible when considering the proportion of IFN-γ+ IL-17A+ T cells found in the inflamed CNS or colon. The generation of these cells was recently shown to fully rely on IL-23 signals in the context of inflammatory bowel disease (IBD) [80]. Given the unaltered numbers of both IL-17A+ and IFN-γ+ single producers, but the striking difference in tissue pathology observed in the absence of IL-23 signaling, these IFN-γ+IL-17A+ T cells might represent the pathogenic population of T cells induced by IL-23. It is most likely the case that IL-23 acts on newly generated IL-23R-expressing Th17 cells and causes a shift in function, recognizable, and detectable by an increase in IFN-γ production [79, 81]. This is somewhat of a paradox, given that few molecules show a more potent inhibition of Th17 generation than IFN-γ, and that anti-IFN-γ must be added to T-cell-polarization cultures designed to induce GM-CSF production [78].

Looking past Th17 cells: IL-23 and γδ T cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References

After the arrival of additional tools such as IL23R-reporter mice, it became clear that IL-23 acts not only on conventional αβ T cells, but also on cells of the innate immune system. Different types of innate lymphocytes have been shown to react rapidly to stimulation with IL-23, and much like activated αβ T cells, will respond by secreting an array of pro-inflammatory cytokines including IL-17A, IL-17F, and IL-22 [63, 82-85]. In particular, γδ T cells moved into the spotlight after it was reported that these cells constitutively express the IL-23 receptor [86], while conventional αβ T cells require prior stimulation with IL-6 and IL-21 Though being present in comparably small numbers in the lymphoid compartment (reviewed in [87]), γδ T cells are proportionally enriched within epithelial cell layers in the skin and gut, where they are likely to be the first cells to respond to IL-23. Hence, the immediate cytokine secretion by γδ T cells after exposure to IL-23 might play a crucial role in shaping the emerging adaptive immune response.

In line with this hypothesis, it has been shown that during the course of EAE, γδ T cells were the first IL-23 responders and accumulated in the CNS, particularly during early stages of the disease. Of note, using several in vitro and in vivo approaches, Petermann et al. [88] showed that γδ T cells inhibit Treg function, thereby explaining the ameliorated EAE disease course in T-cell receptorδ knockout animals. On this evidence, one can imagine an innate mechanism by which γδ T cells suppress Treg cells in an IL-23-dependent fashion. The gut and associated tissues represent the organ with the highest level of IL-23 production, most likely due to the proximity of the microbiota in the gastrointestinal tract. The high levels of IL-23 expression seen in the gut may suppress Treg responses via γδ T cells to allow adaptive immunity to ensue in response to a gut-related infection.

There is one obvious question arising from these studies: are the target cells of IL-23 in the experimental setting of autoimmune neuroinflammation merely αβ T cells or also γδ T cells? Studies using adoptive transfer of myelin oligodendrocyte glycoprotein (MOG)-specific IL-23R−/− T cells concluded that only αβ T cells are relevant [32]. However, many current adoptive transfer protocols rely on prior in vivo immunization and it cannot be excluded that during this priming period, IL-23-responsive innate immune cells such as γδ T cells shape the developing αβ T-cell response by modulating the local cytokine milieu. In order to unequivocally clarify this question, a conditional IL-23R allele would be necessary.

Despite their low numbers, γδ T cells have been shown to be major contributors to IL-17 production not only during CNS inflammation, but also in other models of autoimmune disease. In a model of CIA, γδ T cells were responsible for the majority of IL-17 expression. In this particular setting, IL-17 expression was induced by IL-23- and IL-1-triggered signaling in γδ T cells [89]. Very recently, the pathogenic role of the IL-23–γδ axis has been highlighted in another disease model, namely imiquimod-driven psoriatic skin inflammation [90, 91]. This finding is of particular importance, since psoriasis has so far been considered to be a CD4+ T-cell-mediated disease, with treatment strategies aiming at targeting conventional CD4+ Th17 cells. However, the data by Yan and colleagues [88] suggest that γδ T cells are the predominant source of IL-17 not only in the mouse model, but also in psoriatic lesions from human patients and it is known that IL-17 contributes greatly to psoriatic disease progression [92-95].

From adaptive to innate immunity: IL-23 and ILCs

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References

Shortly after IL-23 was identified as the major pathogenic messenger in EAE [25], various human immunopathologies previously ascribed to the action of IL-12-activated Th1 cells were probed for the involvement of IL-23. Consequently, it was shown by several groups in mouse models of IBD that IL-23 is indispensable for immune-mediated destruction of the intestine [52, 96, 97]. Furthermore, in a genome-wide association study in IBD patients, several single nucleotide polymorphisms in the IL23R gene were associated either with resistance or susceptibility to IBD [48]. Interestingly, polymorphisms in the IL-12Rβ1 and the IL-12p40 subunit did not associate significantly with the disease. Given the therapeutic options, this observation intensified efforts to understand the exact role of IL-23 in intestinal inflammation. Initially, most of the research focused on the involvement of Th17 cells, which were identified at the same time, and were also shown to contribute to the disease in various mouse models. However, it was puzzling that the injection of an agonistic anti-CD40 antibody into RAG−/− animals was also able to cause IL-23-dependent gut pathology, suggesting an important role for innate non-T/B cells in intestinal autoimmunity [97]. In this model, the IL-12 family members had strikingly differential roles: while IL-23 was nonredundant for the development of colitis, only IL-12 perpetuated the accompanying systemic inflammatory response and wasting disease.

The cell type responsible for the CD40-driven intestinal inflammation was not identified until recently, when Powrie and colleagues showed that a novel population of gut-resident Thy1+ Sca1+ RORγt+ innate lymphoid cells (ILCs) responds to IL-23 [98]. Mechanistically, IL-23R signaling activated expression of IFN-γ and IL-17 by ILCs, and neutralization of these cytokines strongly ameliorated the disease course [95]. Depletion of ILCs using an anti-Thy1 antibody almost abrogated colon inflammation, while the systemic wasting disease remained unaffected.

When comparing the action of IL-23 on αβ T cells, γδ T cells, and ILCs, there seems to be a remarkable conservation in function, with all three cell types responding to IL-23 by production of proinflammatory cytokines such as IL-17, IL-22, and IFN-γ (Fig. 2). Thus, innate cells such as ILCs might be part of an early, immediate tissue inflammatory response, while T cells respond to IL-23 later in an antigen-dependent fashion.

Of note, the (at least partially) IL-23-driven effector cytokines IL-17 and IFN-γ seem to play completely divergent roles in different autoimmune settings: while neither of these cytokines are essential for disease progression in EAE [55, 56, 99], their neutralization in innate IBD strongly ameliorated the disease [98]. These differential results of cytokine depletion do not come as a surprise given the distinctive lymphocyte composition in the brain and the gut, but emphasize that the downstream effects of IL-23R engagement are highly dependent on the targeted cell population and the target organ. Very recently, it has been suggested that ILCs could also contribute to skin inflammation by IL-23-driven production of IL-22 [84]. However, whether IL-23-mediated activation of ILCs is involved in additional immunopathologies remains to be determined and requires a more thorough understanding of the function of ILC populations during immune responses.

IL-23 and beneficial self-destruction: Targeting tumors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References

When considering self-reactivity of the immune system and autoimmune destruction of healthy tissues, one must also consider the beneficial aspect of anti-tumor immunity [100]. T cells are known to play an important role in early-stage control of tumor growth, and some T-cell-derived cytokines such as IL-17 and IFN-γ are thought to have anti-tumor activity. For this reason, IL-23 has also been studied for its potential function during an anti-tumor response. Initial reports using IL-23-transfected tumor cell lines suggested an anti-tumorigenic function similar to that of IL-12 [101]. However, this notion was challenged by a subsequent report, in which p19−/− animals were tested for their susceptibility to chemically induced tumor formation [102]. Strikingly, in these mice tumor burden was strongly reduced when compared to wild-type or p40−/−controls, arguing for a pro-tumorigenic role for IL-23, which was ascribed to a reduced infiltration of cytotoxic CD8+ T cells into the tumor.

Given the prominent function of IL-23 during the differentiation of Th17 cells, many researchers focused on the role of Th17 cells in tumor development, but contradictory results have been reported. While several groups attributed increased tumor-killing activity to Th17 cells in both subcutaneous and metastatic mouse melanoma models [103, 104], others have reported the opposite: in a transgenic model of spontaneous intestinal tumorigenesis, the lack of IL-17 abrogated tumor progression [105], and some metastatic melanoma models argue for a pro-tumorigenic function of IL-17 [106], which would fit the data obtained with p19−/−knockouts. The general consensus seems to argue for tumor-promoting functions of both IL-23 and IL-17, if anything, but further work is needed to clarify their precise roles in anti-tumor immunity.

Of note, the presence of GM-CSF has been shown to be beneficial in vaccination approaches during subcutaneous tumor growth [107]. Given that GM-CSF can be expressed in an IL-23-dependent fashion by CD4+ T cells, this might be another potential mechanism by which IL-23 can modulate tumor immunosurveillance.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References

The seemingly ubiquitous presence of IL-23 in inflammatory autoimmune disease models and its importance for the associated pathogenesis has significantly elevated the status of this cytokine. IL-23 has undoubtedly risen to prominence because of its unique ability to transform an activated T cell into an encephalitogenic, pro-inflammatory, and potentially self-harming effector cell. Indeed, IL-23 is perhaps the closest immunologists have come to identifying the "magic bullet" responsible for autoimmune disorders. This observation has already been translated into a successful clinical application, at least in the treatment of psoriasis.

On the other hand, the initial model of IL-23 only being implicated in the generation of Th17 cells has proven exceedingly (over) simplified. Not only does IL-23 induces a pathogenic T-cell program involving effector cytokines beyond the IL-17 family, but it also acts on additional innate cell types such as γδ T cells and ILCs. Furthermore, the regulation of IL-23 expression itself remains incompletely understood. As the complex network of IL-23-initiated cellular activity becomes more detailed, we will no doubt uncover more features of this cytokine governing the transition from antigen-specificity to auto-aggression.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Poles apart: Antigen-presenting cells dictate the differences
  5. Sensing IL-23: Permission to be pathogenic
  6. IL-23 as a therapeutic intervention point
  7. All bark and no bite: Hallmark cytokines and misnomers
  8. IL-17A, but no pathogenicity: The difference is in the differentiation
  9. Looking past Th17 cells: IL-23 and γδ T cells
  10. From adaptive to innate immunity: IL-23 and ILCs
  11. IL-23 and beneficial self-destruction: Targeting tumors
  12. Concluding remarks
  13. Acknowledgements
  14. Conflict of Interests
  15. References
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Abbreviations
IBD

inflammatory bowel disease

ILC

innate lymphoid cell