Editorials and Perspectives: Overview
The Emerging Role of TH17 Cells in Organ Transplantation
Sullivan, Jeremy A.1; Adams, Andrew B.2; Burlingham, William J.1,3
1 Department of Surgery, Transplant Division, University of Wisconsin, Madison, WI.
2 Department of Surgery, Emory University Medical School, Atlanta, GA.
3 Address correspondence to: William J. Burlingham, Department of Surgery, University of Wisconsin, Madison, WI.
This work was supported by National Institutes of Health grant 1PO1AI084853-01, the EU-sponsored One Study, by a UW-Madison Department of Surgery Research grant (J.A.S. and W.J.B.), and by National Institutes of Health grant U19 AI051731 (A.B.A.).
The authors declare no conflicts of interest.
Received 24 April 2013. Revision requested 14 May 2013.
Accepted 29 August 2013.
Accepted November 8, 2013
While transplantation research continues to focus on the development of Treg-sparing and plasma cell/B-cell–targeting strategies to improve long-term outcomes, little attention has been paid to the emerging role of the TH17 cell in mediating chronic rejection. This review aimed to summarize the recent emergence of the TH17 and the newly described TH1/17 cell as major players in transplantation and to suggest ways of improving graft outcome through TH17-targeted immunosuppression.
Discovery of the TH17 Cell
Interleukin (IL)-17 and some of its effects have been described as early as 1993 (1–3). However, T helper 17 (TH17) cells were actually discovered quite by accident more than 10 years later (4). Their discovery was secondary to an investigation of the role of myeloid cell products, in particular, the IL-12 family of cytokines in the well-characterized mouse model of experimental autoimmune encephalomyelitis (EAE) (4). Experimental autoimmune encephalomyelitis, a model for multiple sclerosis, had long been thought to be a TH1-mediated autoimmune demyelinating disease. The classic model of TH1/TH2 differentiation of naive T-cell precursors developed by Mosmann and Coffman (5) held that the development of TH1 cells, CD4+ T helper cells that produced IL-2 and interferon (IFN) γ and mediated delayed-type hypersensitivity (DTH) required IL-12 production by macrophages or dendritic antigen-presenting cells. TH2 cells, which made the cytokines IL-4, IL-13, and IL-5, providing help for IgE production by B cells and mediating atopic responses, required IL-4 but not IL-12. Experiments using mice that lacked the ability to make different subunits of the IL-12 dimer found that C57BL/6 mice deficient in the p40 subunit of IL-12 were unable to develop EAE unlike their WT-EAE-susceptible counterparts (6). While this result, consistent with the hypothesis that EAE was TH1 mediated, was not surprising, mice that were deficient in the p35 subunit of IL-12 were susceptible to developing EAE, whereas targeted deletion of p19, a subunit of IL-23, completely abolished EAE susceptibility (6). The sum of these studies negated the prevailing idea that EAE was a TH1 disease since neither TH1 nor TH2 was sufficient to describe the induction of the autoimmune pathology in this model. The T cell responsible for the phenotype turned out to be one in which the signature cytokine was not IFNγ, but rather IL-17. Henceforth, this cell was termed TH17 (7).
The connection between IL-23 and the TH17 cell differentiation pathway, as well as the latter cells’ connection to the EAE, antifungal immunity, and transplant rejection, has turned out to be rather complex: not nearly as straightforward as the connection between IL-12 and TH1 induction. This complexity is perhaps one reason why the TH17 cell was not identified until nearly 3 years after the discovery of the IL-23/EAE connection (6) in the works by Harrington et al. (8) and Park et al. (9). The requirements for TH17 cell differentiation have been worked out separately in the human system by Sallusto et al. (10) and in the mouse by Kuchroo and Awasthi (11). One of the key hurdles in identifying the TH17 cell was that IL-23, unlike IL-12, was a maturation factor required for immature TH17 cells to become pathogenic (6, 12), but unlike IL-12 and TH1 cells, IL-23 had no role whatsoever in the initiation of the TH17 pathway. This initiation factor turned out to be the job of cytokines transforming growth factor (TGF) β, IL-6, and IL-1β. Interestingly, TGFβ1, the same cytokine responsible for induction of antigen-specific Treg cells from conventional (CD4+CD25− precursor T cells in the presence of IL-2 (13), drove the differentiation of TH17 cells in the presence of IL-6, or alternatively, the TH17 product IL-21. These “immature” TH17 cells had different nuclear transcription factors from classical TH1 cells, namely, RORγt and STAT3 in lieu of T-Bet and STAT4 (9, 14–16). However, the critical role of IL-23 was not observed until a second, final differentiation step from the immature state to the mature TH17 cell. This second phase of TH17 cell development is mediated by an IL-23/IL-23R interaction. IL-23 binding to its receptor on the T cell has recently been found to induce an autocrine loop involving TGFβ3 (11). TGFβ3 is able to alter SMAD expression profiles, especially Smad1 and 5 levels as well as their posttranslational modifications, allowing full effector TH17 functional differentiation (17). Characteristic features of these fully mature TH17 cells include (a) production of IL-22, a cytokine critical for DTH responses in the vicinity of the epithelium (to understand how expression of IL-22 is controlled in T cells via the aryl hydrocarbon receptor, please see the recent excellent review by Voorhis et al. ); (b) expression of the chemokine receptors CCR6, 4, and 10 (4, 19); and (c) a loss of IL-10 production (20–22).
Interplay of Innate and Adaptive Immunity in TH17 Responses
Figure 1 gives an overview of TH17 development in the human immune response to collagen type V (Col V), a self antigen of critical importance in lung transplantation (23). We now know that there are at least two distinct types of the TH17 cell: the “classic” TH17 cell (top right) and the closely related TH1/17 cell (bottom right). Both TH17 types may be induced from naive T cells by antigen presentation in the context of low levels of TGFβ1 and high levels of IL-6. The sources of IL-6 are various—here a tissue parenchymal cell is depicted as providing IL-6, but monocytes and endothelial cells may also be the IL-6 source. LAIR-1, an inhibitory non-integrin collagen receptor highly expressed on naive T cells and myeloid cells (24, 25), is pictured here inhibiting a monocyte (lower left). Partial disruption and repair of the extracellular matrix collagen of the lung transplant during ischemia-reperfusion injury lead to exposure of Col V from the interior of collagen I-rich fibrils and release of Col V fragments (26), which may activate monocytes via DDR-1 or C-lectin type receptors. While nonactivated circulating monocytes that produce IL-12 promoted TH1 development, Acosta-Rodriguez et al. (27) have reported that LPS or peptidoglycan-activated monocytes and conventional dendritic cells producing large amounts of IL-1β and IL-6 were the most successful at initiating TH17 development in humans (27). Furthermore, antibodies to IL-1β and IL-6 and inhibitors of caspase-1 all blocked TH17 differentiation. While it seems that monocytes and potentially monocyte-derived IL-1β and IL-6 are required for TH17 development, further evidence from our laboratory has also implicated a requirement for monocytes and IL-1β in TH17 effector function (23). In a clinical study, cellular immunity to Col V was found to be a risk factor for the development of severe (odds ratio, 9.8) bronchiolitis obliterans syndrome (BOS), the leading cause of lung transplant graft loss. In peripheral blood mononuclear cells (PBMCs) from lung transplant patients sensitized to Col V, we were able to show that the Col V response, unlike the tetanus toxin (TT) TH1 recall response, was not blocked by IFNγ-neutralizing antibody. Instead, the Col V-specific trans vivo delayed type hypersensitivity assay (tvDTH) response was sensitive to the neutralization of IL-17. While removal of CD4, but not CD8, T cells from PBMC abolished the response both to TT and to Col V, the unique role of innate immunity in the response to Col V was brought to light by the striking inhibition of the anti-Col V, but not the anti-TT response, when IL-1β or tumor necrosis factor α was neutralized and when CD14+ monocytes were removed from PBMC (23). This report as well as a follow-up study analyzing pretransplant Col V reactivity in relation to primary lung allograft dysfunction (28) clearly showed that while IL-17A and CD4 T cells were necessary for the Col V-specific tvDTH response, monocytes/macrophages and their cytokine products were also required.
Figure 1 also shows that TH1/17 cells, producing both IFNγ and IL-17, form a distinct subset of the TH17 family. One of the most important factors in the development of the TH1/17 cell in humans is IL-1β. IL-1β can be produced by monocytes, macrophages, neutrophils, dendritic cells, and Langerhans cells (29–31). A common avenue for the release of IL-1β in monocytes and macrophages is through inflammasome activation and possibly through activation of the P2X7 (32). The role of purinergic signaling and immune cell regulation is a topic under considerable investigation. Extracellular ATP binding to the P2X7 initiates a conformational change in the receptor allowing cations, including potassaium and calcium, to travel into the cell (32–34). Concomitant to P2X7 activity, LPS activation of pattern recognition receptors, including damage-associated molecular patterns (DAMPs) and/or pathogen-associated molecular patterns can signal in concert with the P2X7 leading to downstream inflammasome activation (35). While the inflammasome consists of multiple subunits, successful inflammasome assembly with members of the caspase family of enzymes promote cleavage of pro-IL-1β and release of mature IL-1β and IL-18 from monocytes and macrophages (36, 37). Purinergic signaling is thus an area of convergence between innate immunity and TH1/17 development and function. This convergence is illustrated in Figure 1 by the activation of monocyte/macrophages in the disrupted matrix of the ischemic reperfused organ via matrix-derived DAMPs interacting with DDR-1 (expressed on activated monocytes and smooth muscle cells ) or c-type lectin on myeloid cells. The engagement of extracellular ATP via the P2X7 and potentially other purine receptors promotes the production of IL-1β and IL-18, further driving the differentiation of TH1/17 cells (bottom right). At the level of the mature TH17 effector cell, DAMPs activity may no longer be necessary to initiate a TH1/17 or TH17 response, as peptide recognition by the TH17 cell is sufficient to initiate P2X7 activity and IL-1β release (Sullivan et al., unpublished observations). Because high levels of extracellular ATP binding to the P2X7 will cause increased levels of IL-1β, recently activated T cells would have at least one factor favoring TH17 and antagonizing TH1 development (10).
We have recently studied the effects of inhibition of the P2X7 in PBMCs from Col V-sensitized patients. We found that Col V alone can stimulate IL-1β production in isolated monocytes, consistent with the idea that Col V itself, normally sequestered within the collagen I fibrils of the ECM (39), may be one of DAMPs released during tissue injury (Fig. 1, lower left). We also found that P2X7 inhibitors blocked Col V-stimulated IL-1β production in monocytes. Since IL-1β is required for the TH17 or TH1/17-mediated tvDTH responses to Col V, but not for the TH1-mediated recall response to tetanus toxoid antigen (23, 40), the prediction would be that inhibition of the P2X7 would block the former but not the latter. This is indeed what we have recently found (Sullivan et al., unpublished observations), consistent with the idea that IL-1β, in this case monocyte inflammasome derived, is critically important for TH17 effector responses. The critical role of IL-1β production from inflammasome activation in humans was illustrated in a recent study by Lasiglie et al. (41), which showed that mutations in a common component of inflammasomes, NLRP3, leads to enhanced TH17 responses through an increase in IL-1β production. This naturally occurring NLRP3 mutation, found in cryopyrin-associated periodic syndrome patients, drastically altered the IL-23/IL-17 frequencies, favoring a strong TH17 phenotype and leading to an enhanced inflammatory state. Candida albicans is the most common invasive fungal pathogen in solid organ transplantations outside of lung (42–44). Candida in the hyphal, but not yeast, stage was able to elicit an increase in IL-1β from monocyte-derived macrophages through the interaction of pathogen-associated molecular patterns binding to pattern recognition receptors and activation of the inflammasome pathway (45). The observations in the Candida infection model raises a question as to whether the physical shape/conformation of antigens, self or foreign, may make them more likely to activate antigen-presenting cells to produce IL-1β, which, in the context of peptide/MHC presentation to naive T cells, will drive them toward becoming TH17 or TH1/17 cells. It is possible that certain self antigens, like the α1 chain of Col V, which contain extensive posttranslational modifications (39), or k-α1-tubulin, which along with Col V, is a key self antigen driving TH17 and antibody responses in obliterative airway disease models and human lung transplant BOS (46), may possess inherent DAMPs. Such antigens, being filamentous and decorated with various carbohydrate motifs, may provide a particularly strong signal to innate immune cells. Thus, the T cells recognizing self peptides from these antigens may be prone to arise during homeostatic remodeling.
Inhibition of TH17 Cells by CD39+ Regulatory T Cells
Recent observations in models of autoimmunity have revealed the importance of CD39+ Tregs in regulating the response to self antigens (47–50). The ectonucleotidase, CD39, is the rate-limiting enzyme in the hydrolysis of extracellular ATP. Because CD39+ cells could control the relative levels of extracellular ATP, it is possible that the interplay between the activated monocyte-producing IL-1β, the CD39+ Treg, and the TH17-like cell will all determine whether a self antigen is able to drive development of pathological TH17 or TH1/17 cells. The homeostatic equilibrium between immature TH17 cells and CD39+ Treg cells is illustrated in the center of Figure 1. The production of adenosine by the breakdown of extracellular ATP via CD39 and CD73 (51) as well as the production of TGFβ1 at high levels (10) and IL-35 (52) by the CD39+ Treg cells are three possible avenues of its suppressive effects on immature TH17 cells. The CD39+ Treg cell (top, center) is shown as possibly coexpressing Foxp3 and the characteristic TH17 nuclear factor RORγT, based on the recent findings of Duhen et al. (53).
Evidence for TH17 in Transplant Rejection
Ischemia/reperfusion injury during transplant surgery exposes tissue DAMPs, including ATP itself, and molecular patterns found on certain sequestered antigens such as Col V (26), vimentin (54), or k-α-tubulin (55) in the extracellular matrix. These conditions may preferentially bias the local immune response to these sequestered antigens, as well as the indirect alloresponse response toward a TH17 or TH1/17 T-cell phenotype, dramatically reducing the long-term success of organ transplantation in the calcineurin inhibitor (CNI) era of immunosuppression. What is the evidence that TH17 cells do indeed impact a heart, lung, liver, pancreas, islet, or kidney allograft? Until recently, experimental transplantation models to study T-cell function in graft rejection and tolerance were predominantly mouse models of skin and heterotopic heart allografts across MHC plus non-MHC barriers. These types of allografts typically engender acute TH1 responses, which may be effectively controlled by CNI drugs, co-stimulation (CoS) blockade, and Treg cells.
Research in adaptive immunity in human and nonhuman primate transplantation has been dominated by studies of PBMCs of kidney, liver, and heart transplant recipients using in vitro tests such as the mixed lymphocyte reaction, cytotoxic T lymphocyte, and IFNγ or IL-2 ELISPOT assays. These assays mainly detect the high-frequency direct pathway of alloreactivity. The direct pathway, which may derive from inherent molecular properties of T-cell receptor-p/MHC interaction (56, 57), is highly enriched in TH1 cells due to cross-reactivity of viral antigen-specific T memory cells with allo-MHC (58, 59). Meanwhile, the importance of the much lower-frequency indirect pathway, the recognition of allopeptides in the context of self MHC (60, 61), and the closely related pathway of self antigen-derived peptide/MHC reactivity engendered by the allograft (26, 62) have only recently been appreciated (63) due in large part to the development of the tvDTH assay in 1999 by Carrodeguas et al. (64). Given this new tool, the indirect pathway of alloreactivity, as well as self antigen reactivity in transplant patients, was now accessible to study without reliance on any particular cytokine readout. Using the tvDTH test, it was possible not only to identify novel donor antigen-specific Treg cells secreting IL-10 and active TGFβ1 in tolerant patients but also to explore pathways of T-cell–mediated immunity mediated by molecules other than IFNγ (65).
The lung transplant has a particularly strong tendency to develop chronic rejection, which manifests as BOS, causing the loss of 50% of grafts by 5 years after transplantation (66). BOS is defined in pulmonary function tests as the loss of 20% of forced expiratory volume in 1 sec from the maximal posttransplant value. Whereas 20% loss may reflect other things besides obliterative bronchiolitis, progression to a 35% or 50% loss of forced expiratory volume in 1 sec (BOS level 2 or 3) is a sure sign of the terminal phase of obliterative bronchiolitis (OB). Using the tvDTH test, we found that the appearance of reactivity to Col V in PBMC at 1 year after transplantation was associated with a nearly 10-fold increased risk for development of BOS level 2 or 3 (23). Because the tvDTH response to Col V in lung transplant patients was inhibited strongly by IL-17, but not by IFNγ antibody, we concluded that BOS-associated anti–Col V cell-mediated immunity was a TH17 phenomenon. Our conclusion was further supported by Vanaudenaerde et al. (67), who found that bronchioalveolar lavage cells from patients with BOS had a 10- to 20-fold elevation in IL-17A and IL-23 mRNA levels, relative to stable lung transplant patients. The same was not true for patients with acute rejection. Finally, the recent development of a lung transplant OB model in the mouse by Fan et al. (68) avoided severe acute rejection by using MHC-matched, minor H-mismatched strains, C57BL/10 and C57BL/6, as donor and recipient. This allowed development of fibro-obliterative OB lesions in approximately 50% of the mice by days 1 to 28. Remarkably, the OB lesions were completely prevented by administration of an IL-17R/Fc fusion protein (68).
The recognition of TH17 cells as critical players in the chronic rejection of nonpulmonary transplants has developed much more slowly. Part of the reason for this is the delayed recognition of the role of IL-1β and the TH1/17 cell as a distinct subset of the TH17 response. Rather than being an extension of the TH1 response, which is highly sensitive to CNI inhibition, the TH1/17 cell is clearly part of the IL-17/IL-23 axis that is relatively CNI-resistant. The allo-indirect pathway response, so critical for late acute and chronic rejection of heart and kidney transplants (69, 70), turns out to be highly enriched in donor-specific TH1/17 cells (71). Interestingly, we observed a similar TH1/17 indirect pathway response to donor alloantigens in a heart transplant patient with acute rejection and advanced cardiac allograft vasculopathy. This patient also had a TH1/17 response to the self antigen Col V (Burlingham et al., unpublished observations). It is likely that the type of immune response to allopeptides, and to self antigens, whether TH17, TH1/17, or TH22, is dependent on the cytokine milieu of the affected organ. Consistent with this idea, coronary artery disease resulting from atherosclerosis was correlated with a TH1/17 response to Col V (40), rather than the purely TH17 response to Col V seen in pulmonary disease and lung transplant BOS (23, 28).
The use of CoS blockade may also drive T-cell differentiation by altering the quality of signals received during T-cell activation. This may in turn alter T-cell programming, local cytokine milieu, and others, which may ultimately push development toward one T-cell subset or another, i.e., TH1, TH17, or TH1/TH17.
Control of TH17 and TH1/17 –Mediated Rejection After Transplant
The foregoing raises the question: How can we do a better job of controlling TH17- and TH1/17-mediated immunopathologies that compromise long-term outcomes in our transplant patients? The recent work of Vergani et al. (72, 73) showed an increase in P2X7+ T lymphocytes in both mouse and human cardiac transplant infiltrates during rejection and in PBMCs of long-term pancreatic islet allograft recipients with failing glucose control. Treatment of mice with oxidized ATP, an inhibitor of P2X7, inhibited in vivo TH1/17 responses and prolonged both islet and heart allografts (72, 73). These data, combined with our recent finding of the preferential suppression of TH1/17 and TH17-mediated—but not TH1– tvDTH by P2X7 antagonists (Sullivan et al., unpublished observations), suggest that targeting the P2X7 is a potentially attractive approach that could be effective in preventing chronic rejection in organ and tissue transplant recipients.
Another strategy is to attempt to starve the TH17 cells of IL-23, relegating them to the relatively harmless “intermediate” status and preventing their progression to pathologic effector/memory TH17 cells (Fig. 1). This strategy has recently been applied to costimulation-resistant rejection in nonhuman primates treated with belatacept, the high-affinity version of CTLA4-Ig, recently approved for use in kidney transplant recipients. Studies at Emory University by Kitchens et al. (unpublished observations) demonstrated that the use of belatacept monotherapy for immunosuppression in kidney transplants greatly reduced the IFNγ component of the alloresponse in nonhuman primates but unexpectedly markedly increased an IL-17A response. While costimulation blockade effectively inhibited the allo-TH1 response, an unintended consequence was the induction of a TH17-mediated antidonor response. Subsequent mouse studies demonstrated that the pairing of CoS blockade and an anti–p19/IL-23–specific antibody to target the TH17 response prevented rejection and prolonged survival.
Besides blockade of pathways leading to pathogenic TH17 effector cell development versus allo-antigen and to self antigens overexpressed in the transplanted organ, a different approach, to inhibit the downstream pathways of IL-17 receptor signaling, has been used in the lung transplant recipient. Macrolide antibiotics, such as azithromycin and erythromycin, were initially used simply to treat bacterial infections in lung transplant patients in the 1990s. It was later discovered (serendipitously!) that the agents were actually blocking progression of BOS. This leads to in vitro analysis of the effects of azithromycin on bronchial epithelial cell production of IL-8 and lipid mediators of neutrophil recruitment in response to IL-17A. While CNI, steroids, and other commonly used immunosuppressive drugs had no effect or had not stimulated the IL-17R signaling pathway, macrolides azithromycin and erythromycin effectively blocked IL-17–stimulated IL-8 secretion by bronchial epithelial cells (74). Interestingly, the widespread use of azithromycin in cases of BOS has revealed a dichotomy in BOS diagnosis. Some patients, with a more neutrophilic form of OB/BOS, respond well to treatment, showing improvement of pulmonary function along with clearance on neutrophils from the bronchioalveolar lavage. Others, with a more advanced, fibroproliferative form of OB, were resistant to the same therapy (75).
This review has attempted to summarize what is known about the role of TH17 cells in rejection of transplants. Understanding the nature of the TH17 threat to the transplanted organ is already leading to new immunosuppressive strategies, but transplant practitioners have only scratched the surface of its importance in humoral immunity; for example, the role of TH17- and T follicular helper cell-derived IL-21 in driving B-cell responses to the allo antigen and tissue/self antigens of the graft. Recent reports in mice have also surfaced linking induction of TH17 cells to SGK-1, a salt-sensing kinase (76). These studies may have clinical implications, including linking IL-17 induction to hypertension, type 2 diabetes, and chronic rejection. Finally, it should be noted that the most effective therapy for preventing TH17-mediated rejection remains the maintenance of strong Treg control over the intermediate-stage TH17 cells. As shown in Figure 1, the most effective Treg cells in this regard are the CD39+ Tregs (49). These T cells may arise in the thymus as “natural” Tregs, acquiring CD39 expression in the periphery as they encounter self antigen, or they may be induced by encounter with alloantigens in the periphery. These Tregs may be maintained in some patients, preventing progression of chronic rejection. Importantly, we must consider that, in some patients, these critical CD39+ Tregs may be lost, especially under conditions of allo-antigen and self antigen stimulation arising from the ischemically injured/repaired transplant, coupled with chronic CNI immune suppression. Recent efforts to augment Treg cells and regulatory macrophages (mRegs) at the time of kidney transplant, along with more “reg cell-friendly” approaches to immunosuppression, are important first steps that will undoubtedly bear fruit in the future prevention of TH17-mediated transplant loss (77).
The authors would like to acknowledge Carol Dizack for her artistic contributions to this article and David S. Wilkes and Daniel S. Greenspan for helpful discussions of the model.
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TH17; monocytes; P2X7; IL-23; transplantation; collagen type V
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