American Journal of Respiratory and Critical Care Medicine

During T-cell receptor activation in a particular cytokine environment, naive CD4+ T cells may differentiate into lineages defined by their pattern of cytokine production and transcription factors: T helper type 1 (Th1), Th2, Th17, and Th22 cells; follicular helper T cells; and inducible regulatory T cells. Th17 cells have been recognized as a distinct lineage of Th cells, and associations between IL-17 and human disease have been known somewhat longer. It would be an oversimplification to restrict IL-17 to Th17 cells. Indeed, IL-17 is also expressed by other cells including IL-17–producing γδ T (γδ T-17) cells, natural killer T-17 cells, and IL-17–producing lymphoid tissue–induced cells. IL-17 was cloned in 1995 as a cytokine expressed by T cells, exerting inflammatory effects on epithelial, endothelial, and fibroblast cells. IL-17 is a solid link between innate and adaptive immunity and can exert both beneficial and deleterious effects. The discovery of IL-17 T cells has provided exciting new insights into host defense, immunoregulation, and autoimmunity. Unquestionably, data from mouse models have contributed enormously to our insight into immunological mechanisms. However, because of numerous differences between murine and human immunology, data obtained in mice are not simply interchangeable. We review IL-17 T cells exclusively in the human situation and more specifically their potential role in respiratory diseases. The advances in our understanding of IL-17 regulation offer opportunities to dissect the human IL-17 system and to reflect on the clinical presentation of lung diseases. More importantly, the IL-17 system allows us to speculate on new therapeutic opportunities. Some results have been previously reported in an abstract.

CD4+ T cells are critical in host defense, immunoregulation, and autoimmunity. These T cells differentiate into distinct subsets that produce restricted patterns of cytokines (Figure 1). This allows them to tailor their responses to the character of the threat encountered, providing help to B lymphocytes, CD8+ cytotoxic T cells, and the innate immune system (1). The first step in T-cell activation relates to consequences of signals emanating from T-cell receptor (TCR) occupancy including signature cytokine signals and (master) transcription factors. Helper T type 1 (Th1) and type 2 (Th2) cells were the first CD4+ T-cell subsets described; are under the control of T-box transcription factor (T-bet) and trans-acting T-cell–specific transcription factor (GATA3), respectively; and produce IFN-γ, IL-12, lymphotoxin (LT)-α, tumor necrosis factor (TNF)-α, granzymes, and IL-4, IL-5, IL-6, and IL-13 (2) (Figure 1). Regulatory T (Treg) and IL-17–producing helper T (Th17) cells have changed this concept with their own signature cytokines: IL-10, IL-35, and transforming growth factor (TGF)-β, IL-17A, IL-17F, IL-21, IL-22, and IL-23, and master regulators forkhead box P3 (FoxP3) versus retinoic acid receptor–related orphan receptor C2 (RORC2) (2). Th9, follicular helper T (Tfh), and Th22 (the latter found only in the skin) cells have been described with signature cytokines IL-9, IL-10, IL-6, IL-21, IL-22, and TNF-α and with master regulators GATA3, B cell lymphoma-6 (Bcl6), and aryl hydrocarbon receptor (AhR), respectively (35) (Figure 1). Th1, Th2, and Th17 cells are important for eradicating intracellular pathogens, helminthes, and extracellular bacteria/fungi. In pathological situations, Th1 and Th17 cells are involved in autoimmune diseases, whereas Th2 cells contribute to allergic responses (6) (Figure 1). Treg cells originate from naive precursors in the thymus (natural, nTregs) or are induced in the periphery (induced, iTregs). Tregs provide tailor-made control of the immune response and are critical in maintaining self-tolerance and modulating immune responses to infections (7) (Figure 1). The role of Th9, Tfh, and Th22 cells has not been fully elucidated. Tfh cells aid in the development of germinal centers, secondary lymphoid tissues that promote B cell immunity, and so help B cells to mount antibody responses to T-cell–dependent antigen and to promote immunoglobulin class switch recombination and maturation (4). Consequently, dysregulation of Tfh cells can contribute to autoimmune diseases or immunodeficiency (8). Th22 cells seem to be restricted to the epidermal layer in inflammatory skin diseases and enable epithelial innate immune responses but also wound healing, tissue remodeling, angiogenesis, and fibrosis (9). IL-22 has both proinflammatory and tissue-protective properties depending on the cytokine environment, more specifically depending on the presence or absence of IL-17 (10). The exact role of Th9 cells is not clear. However, they lack a suppressive function yet promote tissue inflammation with mucus hypersecretion (3) (Figure 1).

Th17 cells have received considerable attention. The current concept supports a central role for IL-23 in both maintaining and directing Th17 cell development (11). The combination of IL-1β and IL-6 is essential for proper Th17 cell differentiation. Reports on TGF-β1 are ambiguous: it first appeared to be a repressor of the Th17 cell lineage, and later it seemed to assist the Th17 cell lineage indirectly via Th1 suppression (12, 13). Prostaglandin E2 (PGE2) also promotes Th17 cells by up-regulating the IL-23 and IL-1 receptors (IL-23R and IL-1R, respectively) and by synergism with IL-1β, IL-6, and IL-23 (14) (Figure 1). Transcription factors involved in Th cell differentiation form a sophisticated network with positive and negative feedback loops. At least six transcription factors are linked to Th17 cell fate. RORC2 is the most specific and is known as the master transcription factor (15) (Figure 1). Overexpression of RORC2 induces many features of Th17 cells, but RORC2 alone can induce IL-17 production in only 20% of the T-cell population, confirming the assistance of other transcription factors including signal transducer and activator of transcription-3 (STAT3), interferon regulatory factor-4 (IRF4), runt box transcription factor-1 (Runx1), and AhR to fully develop Th17 cells (2, 16). Th17 cell differentiation is tightly regulated not only positively but also negatively as Th17 is inhibited by IL-2 (produced by iTreg cells), IFN-γ and IL-27 (Th1 cells), IL-4 (Th2 cells), and other negative regulators such as retinoic acid (17, 18) (Figure 1).

Although this scheme of Th differentiation seems complicated, it is mere oversimplification. Activated memory T cells preserve plasticity to alter their cytokine program according to the stimuli received. A cytokine restricted to one Th subset can be secreted by another subset under changing stimulation conditions. Preferential directions for plasticity and the potential of preserved plasticity in effector T cells remain unanswered questions (19). In Th17 cells coproduction of IFN-γ and IL-17 is common. Moreover, Th17 cells can produce IFN-γ and stop producing IL-17, resulting in a complete class switch (1). Plasticity even concerns master regulators: FoxP3 expression within iTreg cells is heterogeneous and transient and former iTreg cells have the capacity to produce proinflammatory cytokines such as IL-17 (19). Moreover, multiple master regulators (along with a mixed cytokine profile) can be expressed, such as a combination of FoxP3 with RORC2 (mixed Treg/Th17) (1). Master regulators can function as transcription factors of other helper T-cell classes; AhR, the master regulator for Th22 cells, is also involved in Treg and Th17 cell induction (20). The expression of master regulators should not be simplified as mutually exclusive but rather as a gradient of transcription factors (1). Plasticity depends on the regulation of transcription factors and repressors, which is controlled by intrinsic and extrinsic signals such as epigenetics and microRNA (19). Plasticity could be an answer to the evolution of pathogens, allowing a proper response to new threats.

IL-17–producing Cells Other Than Th17 Cells

Much emphasis has been placed on the production of IL-17 by Th cells, but Th17 cells are not the only source of IL-17. Within the adaptive arm of the immune system, some cytotoxic T (Tc) cells are also capable of producing IL-17. Tc cells have the ability to cause direct pronounced cytolysis of antigen-expressing target cells, which endows them with the unique ability to survey the host for intracellular perturbations and to restore homeostasis. A subset of Tc cells is observed to produce IL-17 (Tc17 cells) in the lung and digestive mucosa, paralleling the distribution of Tc17 cells, only less abundant. Findings have demonstrated that the development of Tc17 cells mirrors Th17 cell development (21) (Figure 1).

On the other hand, the role of innate immune cells (invariant natural killer T [iNKT] cells, lymphoid tissue–induced [LTi] T cells, and γδ T cells) producing IL-17 is less well understood (Figure 1). The role of these alternative sources of IL-17 should not be neglected as they provide a rapid response (48 h) to pathogens and promote a more potent adaptive immune response, which needs 3 to 5 days to develop. The key feature of this innate IL-17 response is the early neutrophil recruitment. This results in a more efficient resolution of infection, in the maintenance of mucosal barrier integrity, but also in the potential induction of autoimmunity. γδ T cells, members of the innate immune system, do not express classical αβ-TCR but γδ-TCR instead. They bind to epitopes in much the same way as antibodies do. IL-17 production is observed in a subset of γδ T (γδT-17) cells sharing typical Th17 cell transcription factors (RORC2, AhR, etc.), differentiating/stimulating cytokines (IL-1β, IL-6, IL-23) and effector cytokines (IL-17, IL-22) (22) (Figure 1). γδT-17 cells specifically express Toll-like receptor-1 (TLR1), TLR2, and dectin-1 (23) and can activate Th17 cells both directly and indirectly via IL-23 production (22) (Figure 1). Thus, these cells provide a rapidly available source of IL-17 (22). A subset of iNKT cells also produces IL-17. iNKT cells arise from the thymus out of a common precursor pool of CD4+CD8+ double-positive thymocytes. They express a distinct TCR reacting to CD1d associated with glycolipid antigens (24). iNKT cells display features of T cells and NK cells and express the invariant TCR α chain (Vα24Jα18) combined with a limited variation of TCR β chain (usually Vβ11) (25) (Figure 1). Like γδ T cells, iNKT cells play a pivotal role in immunity as they provide a rapid (innate) response within minutes to hours, with the capacity to critically amplify and regulate adaptive immune responses (24). IL-17–producing natural killer T (NKT-17) cells are CD4-NK1.1 and represent a small fraction of NKT cells within the thymus, spleen, liver, and lung, but a larger part of the NKT population in the peripheral lymph nodes (26). NKT-17 cells are functionally divergent and independently regulated from other NKT cells as observed by the specific expression of RORC2, IL-23R, chemokine receptor-6 (CCR6), CD103, and CD121 and by the absence of NK1.1 (26) (Figure 1). NKT-17 cells also produce Th17 cytokines IL-21 and IL-22 (27, 28). Their presence in the periphery (especially the lymph nodes) and selective expression of RORC2 support the concept of a developmentally programmed, distinct lineage that possibly branches early in thymic NKT cell development. The last cell type producing IL-17 in humans is the LTi cell, which represents a primitive precursor of NK, NKT, and CD4+ T cells. Specifically immature (CD127+) NK cells are closely related to LTi cells (29). LTi cells promote the formation of secondary lymphoid tissue and sustain primed CD4+ T-cell memory responses (29). LTi cells are present in postnatal secondary lymphoid tissues such as gut or nasal or bronchial-associated lymphoid tissue, lymph node, spleen, and tonsil (30). Some LTi cells produce LT-α, LT-β, TNF-α, IL-17, and IL-22, the latter two controlled primarily by RORC2. LTi-17 cells can secrete IL-17 after stimulation solely with IL-23 (31) (Figure 1). STAT3 is not involved, which is concordant with the observation that IL-1β, IL-6, and IL-21 are not involved in IL-17 production by LTi cells (31) (Figure 1). Thus, like γδT-17 and NKT-17 cells, LTi-17 cells provide a rapidly available source of IL-17. Other innate IL-17 producers have been postulated such as Paneth cells, NK cells, macrophages, myeloid cells, and neutrophils (32, 33). Yet data are scarce. Overall it is clear that we do not fully appreciate and understand the role of innate IL-17–producing cells in the mucosal tissue.

IL-17 T lymphocytes induce a severe neutrophilic response linked to several chronic inflammatory conditions through the production of IL-17. Several disorders previously classified as typical Th1 disease are now considered to be primarily Th17-driven: rheumatoid arthritis (34), inflammatory bowel disease (35), and psoriasis (36). These conditions are an excellent introduction to the role of IL-17 T cells in lung diseases, as the role of IL-17 T cells in these conditions has been investigated thoroughly. They can inspire us to look at new treatment options such as monoclonal antibody therapies (37) and teach us about environmental and genetic risk factors. For instance, in inflammatory bowel disease or Crohn's disease genetic, correlative, and therapeutic data support the hypothesis that Th17 cells drive the chronic inflammation. At the genetic level, a single nucleotide polymorphism in the IL-23R has proven to be associated with Crohn's disease (38). In general, only Th17 cells are mentioned, creating the false impression that the other innate and adaptive IL-17 T cells (γδT-17, NKT-17, LTi-17 and Tc17) are not contributing to the condition of chronic inflammation (39).

When studying the role of IL-17 T cells in chronic lung conditions several issues need consideration. First, chronic lung conditions previously believed to be Th1 cell disorders deserve special attention as they may be mediated primarily by IL-17 T cells. Second, the anatomical localization of IL-17 T cells (and neutrophils) must be considered. Last, it is crucial to use the appropriate methods. The cytokines of interest are IL-1β, IL-6, IL-17, IL-21, IL-22, and IL-23. To identify IL-17 T cells it is essential to focus on IL-17, IL-23R, and RORC2. However, to discriminate between Th17, Tc17, γδT-17, NKT-17, and LTi-17 cells the focus should also be on TCR patterns in combination with surface markers: for Th17 or Tc17 cells the αβ-TCR in combination with CD4 or CD8, respectively; for γδT-17 cells the γδ-TCR; for NKT-17 cells tetramer staining with CD1d, glycolipid on the TCR α-chain (Vα24Jα18)/β-chain Vβ11 and for LTi-17 cells CD117 and CD127. IL-17 T cells are present in the airway (sub)mucosa whereas neutrophils are present in the airway lumen (40, 41). Therefore histopathological examination is an essential tool for studying IL-17 T cells whereas bronchoalveolar lavage (BAL)/sputum analysis is crucial for estimating neutrophilia. Bronchoscopy-guided biopsy and certainly surgically guided biopsy represent invasive techniques and can be performed only if they contribute to the differential diagnosis. For this reason biopsies in chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), or asthma are much less frequently performed than in the context of lung transplantation and interstitial lung disease. BAL analysis is useful for studying IL-17 T-cell–associated cytokine profiles but most importantly for studying IL-17 T-cell–mediated neutrophilia. BAL is again not commonly performed except in lung transplantation and interstitial lung disease. Blood/serum would be an ideal study object as it is easily accessible, yet solid data on IL-17 T cells and neutrophils are lacking. The methodology to study IL-17 T cells includes mRNA, protein, and cells. Protein measurement is performed mostly on BAL, sputum, or serum but represents only indirect evidence of IL-17 T cells and the technique is limited by the available antibodies. Technically, mRNA quantification by real-time polymerase chain reaction seems more useful as it can be used for various types of samples, and has a low detection limit. However, the direct value of this technique raises questions. Direct evidence of the role of IL-17 T cells can be obtained by immunohistochemistry and by flow cytometry. Immunohistochemistry can locate even single IL-17 T cells to specific sites in lung biopsies and offers information about ongoing inflammation. Immunohistochemistry, however, requires colocalization of several markers, which is difficult and can at best be obtained by fluorescence microscopy (maximum, four parameters). Only IL-17 localization has been reported, demonstrating the limitation of microscopy. The best option is flow cytometry (i.e., fluorescence-activated cell sorting [FACS]), as it can combine more than six different parameters. Identification of distinct IL-17 T cells and even distinct subpopulations is relatively simple for the separate populations. However, FACS is labor intensive, requires higher numbers of cells in suspension, and its application is limited by the availability of antibodies and fluorochromes. FACS analysis has not yet been performed on suspensions made of bronchoscopy specimens, probably because of the low leukocyte yield. The ideal study of IL-17 T-cell immunity would include BAL/sputum (to study neutrophilia and related proteins), biopsies (to study IL-17 T cells and subpopulations by both immunohistology and flow cytometry), and perhaps blood analysis, the potential of which is at present unclear.

In lung transplantation IL-17 has been demonstrated to be involved in ischemia–reperfusion injury (IRI), acute rejection, infection, and chronic rejection or bronchiolitis obliterans syndrome (BOS) (4244). As only IL-17 and related proteins or mRNA were studied, these data indirectly suggest a role for IL-17–producing cells (44). Within these papers IL-17 correlated well with CXCL8 (IL-8) and with airway neutrophilia (Figure 2; phases 1 and 3). In vitro work confirmed that IL-17 orchestrated neutrophilic influx by the production of CXCL8, CXCL1 (GRO-α), and granulocyte-macrophage colony-stimulating factor in airway epithelial cells, smooth muscle cells, endothelial cells, and fibroblasts (45). Although subgroups of IL-17 T cells have not been studied, it could well be possible that different subgroups are involved in IRI, acute rejection, infection, and BOS. Data from fundamental immunological research (see the previous section) suggest that in acute rejection, IRI, or infection the innate IL-17 T cells (γδT-17, NKT-17, and LTi-17) are triggered and cause rapid airway neutrophilia within a few hours (Figure 2; phase 1). This first trigger would give rise to an adaptive immune response including dendritic cells, Th17 cells, and Tc17 cells within the secondary lymphoid organs. Chronic or recurrent exposure to triggers and ongoing mucosal injury is likely to tip the balance from tolerance (Figure 2; phase 2) to immune activation in which the adaptive IL-17 T cells (Th17 and Tc17), supported by their innate counterparts (γδT-17, NKT-17, and LTi-17), will induce the typical severe neutrophilic inflammation of BOS (Figure 2; phase 3) (44). In the end, the uncounterbalanced immune activation will lead to immune dysregulation, which in turn will induce a fibrotic process with infiltration and proliferation of fibrocytes/fibroblasts and with transition of epithelial and mesenchymal cells. Eventually this will lead to airway obliteration/occlusion, resulting in respiratory obstruction and eventually terminal respiratory insufficiency (Figure 2; phase 4) (46, 47). The IL-17 T-cell response may also trigger BOS by facilitating autoimmune responses, as autoantibodies against collagen V have been shown to be involved (48) (Figure 2; phase 3). Like others, we have given little attention to the non-Th17 IL-17–producing cells. However, it should be clear that all IL-17 T cells are likely to be involved but with a predominant role for Th17 cells (Figure 2). An important contribution of our group, against the current consensus, is the recognition of different phenotypes within BOS. The neutrophilic airway inflammatory phenotype (neutrophilic-reversible allograft dysfunction [NRAD]) (40) is exclusively associated with positive IL-17 stainings on transbronchial biopsies (49). We described this IL-17 T-cell–mediated neutrophilia phenotype in the context of characteristic clinical, radiological, and histological features including coarse crackles, increased sputum production, bronchiectasis, BAL/sputum neutrophilia, and the histological presence of bronchiolitis (with lymphocytes and monocytes) (Table 1) (40, 50). This phenotype can evolve to airway wall remodeling and finally airway fibrosis or obliteration. More importantly, it is not restricted to lung transplantation and can be translated to other chronic lung conditions.

TABLE 1. CHARACTERISTICS OF THE IL-17–PRODUCING T-CELL NEUTROPHILIA PHENOTYPE IN VARIOUS LUNG DISORDERS


Feature

Characteristic(s)
InflammationNeutrophils present within the BAL or sputum, monocytes and lymphocytes within the airway mucosa and submucosa on TBB/EBB/OLB and autopsy
ClinicalCoarse crackles, increased sputum production
Contributing factorsPathogen exposure of the lower airway tract, gastro-esophageal reflux, smoking, air pollution, autoimmunity, genetic background
ProgressionSlow progression (several years) inducing airway wall remodeling and eventually fibrosis
MechanisticRepeated mild to moderate triggering of epithelial cells, macrophages, and DCs
HistologicalEarly on, submucosal lymphocytic and monocytic inflammation; later on, lymphoid follicles forming germinal centers (BALT structures) and finally airway wall remodeling and fibrosis
RadiologicalBronchiectasis, mucus plugging, airway wall thickening
Therapeutic
Resistant to high-dose corticosteroids and immunosuppression

Definition of abbreviations: BAL = bronchoalveolar lavage; BALT = bronchus-associated lymphoid tissue; DCs = dendritic cells; EBB = endobronchial biopsy; OLB = open lung biopsy; TBB = transbronchial biopsy.

Also within COPD a potential role for IL-17 T cells has been put forward. COPD is characterized by irreversible airflow limitation due to airway obstruction and emphysematous destruction. Smoking induces a chronic inflammatory response in the central and peripheral airways and in the lung parenchyma, leading to tissue destruction, mucus production, tissue repair, and airway wall thickening/fibrosis. The consensus on the inflammation is that both innate immunity (macrophages, neutrophils, and NK cells), and adaptive immunity are involved (Figure 2). In actuality, the airway neutrophilia leading to airway remodeling and fibrosis mimicks the previously described mechanisms within BOS after lung transplantation. A new element of the axis is lymphoid follicles, a histological hallmark of an adaptive immune response and termed bronchus-associated lymphoid tissue (BALT) collections (Figure 2; phase 3). BALT structures are rare but more abundant in severe and very severe COPD, because of an increased adaptive response against pathogens colonizing/infecting the lower airways (51). BALT can develop in response to microorganisms and foreign particulate matters that gain entry into the lower respiratory tract or in response to autoantigens that develop in repetitively damaged lung tissue (52). The presence of neutrophils and the potential role of autoimmunity (with the presence of B-cell follicles and autoantibodies in the lung and autoreactive T cells in the periphery) indicate CD4+ T-cell involvement in the pathogenesis of COPD (Figure 2; phase 3). In the past, infiltrating CD4+ T cells in COPD were considered to be Th1 cells, but more recently a central role has been attributed to Th17 cells (53). IL-17 T cells in COPD were detected by staining for IL-17, IL-22, and IL-23 on lung biopsies (41, 54). Again, the scatter is tremendous. This could be due to methodological variation, to the various degrees of severity of COPD, or to specific COPD phenotypes. Patients with COPD with a bronchitis presentation with frequent exacerbations and excessive mucus production fit the IL-17 T-cell–mediated neutrophilia phenotype (Table 1). It is clear that also innate and adaptive IL-17 T cells are involved in COPD. Noxious triggers (smoking, autoantigens, the presence of pathogens in the lower airways) are interchangeable between COPD and BOS, which suggests that potentially similar pathophysiological mechanisms are involved in both conditions (53). However, more research is needed to unravel the contribution of the various subsets of IL-17–expressing cells.

It is inevitable that airway infections be discussed, as Th17 cells have a distinct role in host defense against a myriad of bacteria (Escherichia coli, Staphylococcus, Salmonella, Klebsiella pneumoniae, Bordetella pertussis, Pseudomonas aeruginosa) (5557), fungi and protozoa (Cryptococcus neoformans, Pneumocystis carinii, and Candida albicans), and viruses (herpes simplex virus, respiratory syncytial virus, rotavirus, and human leukemia virus type 1) (58). Pathogens induce an IL-17 T-cell response that involves both the innate and adaptive immune system. Human studies are scarce. The best human “model” demonstrating Th17 cell involvement in pulmonary infections is Job's syndrome or the hyper-IgE syndrome, which is caused by a negative mutation in STAT3; as a consequence naive T cells are not able to differentiate into Th17 cells. These patients, without a proper Th17-cell response, are characterized by frequent and severe bacterial and fungal infections (59). Although other factors such as disturbed neutrophil chemotaxis are also involved in hyper-IgE syndrome, the Th17 cell deficiency is striking. The same can be said for patients with chronic mucocutaneous candidiasis. In this condition, the level of peripheral Th17 cells is also low (60). Both conditions suggest an indispensable role for Th17 cells in the host immune system.

Within asthma this specific phenotype is also present. Asthma is characterized by concurrent airway inflammation, cytokine production, and airway hyperresponsiveness to relevant antigens and a specific trigger. The central role of the Th2 subset in the disease, inducing airway eosinophilia and bronchial hyperresponsiveness, is well accepted (53). However, some individuals with asthma display airway neutrophilia (rather than eosinophilia), which correlates with asthma severity (61). This asthma subtype fits the IL-17 T-cell–mediated neutrophilia phenotype. IL-17 both at the mRNA and protein levels is present in breath condensate, sputum, BAL, and biopsies of severe steroid-resistant asthma (62, 63). The cellular source of IL-17 remains unknown.

Another chronic lung disease is CF, characterized by excessive production of aberrantly hydrated mucus in the airways, resulting from mutations in the ion channel cystic fibrosis transmembrane conductance regulator. This increased mucus production blocks normal ciliary function and thus enhances recurrent pulmonary infections. Airway neutrophilia is a feature of CF exacerbations and some patients with CF are predisposed to the IL-17 T-cell phenotype. Sputum IL-17 is up-regulated and correlates with Pseudomonas colonization (64). The mechanisms and features postulated in Figure 2 and Table 1 fit the lung condition in CF. CF is a monogenic disease. However, the role of IL-17 T cells in exacerbations should not be neglected and needs more attention, as it may well offer new therapeutic options in cases of frequent and severe exacerbations.

The group of interstitial lung disorders is difficult to discuss. Wegener granulomatosis, Langerhans histiocytosis, and hypersensitivity pneumonitis have been reported to be linked to IL-17, yet not specifically within the lung. Preliminary data suggest that the axis IL-17 T cells–neutrophilia axis is important in nonspecific interstitial pneumonia, the inflammatory presentations of sarcoidosis, as well as in extrinsic alveolar alveolitis. To gain more insight into the role of IL-17 T cells in interstitial lung disease, we believe it will be crucial to look at subsets of patients, including combined data of lung auscultation (coarse crackles), radiology (bronchiectasis), BAL (neutrophilia), biopsy (IL-17), and risk factors inducing innate immunity (smoking, colonization, reflux, infections) (Figure 2).

Lung cancer is the last group and certainly the most unexpected one. IL-17 was discovered as cytotoxic T lymphocyte–associated antigen (CTLA)-8, similar to the open reading frame 13 of herpesvirus saimiri, a virus capable of inducing T-cell lymphomas in primates. Evidence of the involvement of IL-17 is scarce but existing as IL-17 seems to be involved in non–small lung cancer.

Certainly more research on the immunological basis of lung disease will lead to a better understanding of the role of IL-17 in other chronic lung conditions, not discussed here.

Most critical is the translation of this basic immunology, inflammatory mechanism, and clinical presentation or phenotype into therapeutic options. Again, psoriasis, rheumatoid arthritis, and inflammatory bowel disease can pave the way for IL-17 T-cell–oriented therapy. Unlike previously, we include data from animal models.

Blockade of the Adaptive Immune System
Classical therapy.

Steroids have been the first empirical option when proper treatment is lacking, despite long-term side effects. High-dose steroids are ineffective in severe asthma, the bronchitic form of COPD, CF, and NRAD after lung transplantation, probably because the Th17 cell–neutrophil axis is documented to be steroid resistant (65). Clinical data on nonselective immunotherapy (e.g., cyclosporine) on the IL-17 T-cell–neutrophil axis are not available, but these agents are ineffective in COPD, asthma, CF, and BOS (and NRAD) (66, 67). We believe that nonspecific immunotherapy preferentially inhibits the adaptive immune response, but that the Th17 cell–neutrophil axis is resistant, especially the innate immune cell sources of IL-17 in which CXCL8 production is enhanced by immune suppression (68) The potential for mammalian target of rapamycin (mTOR) inhibitors (i.e., rapamycin) has been put forward in animal models as down-regulators of IL-17 T cells (69), but this has not been confirmed clinically (66). Moreover, rapamycin did not reduce BOS after lung transplantation but, rather, increased adverse events such as bacterial and fungal infections (70). Taken together, experimental studies demonstrated great potential for classical treatments to down-regulate IL-17–producing cells but clinically any potential within the lung is lacking. Extracorporeal photopheresis (ECP) is a form of leukapheresis in which T lymphocytes are inactivate by psoralen and ultraviolet A exposure. ECP is used to treat cutaneous T-cell lymphoma, rheumatoid arthritis, graft-versus-host disease after hematopoietic stem cell transplantation, and BOS after lung transplantation (7173). In graft-versus-host disease, ECP increases Tregs and decreases Th17 cells (74). The potential of ECP in the IL-17 T-cell phenotype in lung disorders has never been documented but perhaps merits further attention.

Cell therapy.

Cell-based immunotherapy is used in cancer therapy, like for non–small cell lung cancer. Immune cells like Tregs, dendritic cells and mesenchymal stem cells are the focus of patient trials in which meaningful clinical impact was achieved (75). FoxP3-expressing Treg cells, which reduce Th17 cells, are an option for cell transfer. In a mouse model of rheumatoid arthritis, transfer of Treg cells inhibited disease progression. Transfer of antigen-presenting cells such as dendritic cells (DCs) could be an alternative. Cell plasticity within Treg and Th17 lineages and especially DCs complicates their therapeutic use as the treatment could backfire and enhance rather than alleviate disease. Mesenchymal stem cells are a heterogeneous population of stromal cells that exert immunosuppressive activities by suppressing T and B cells, dampening mature myeloid DCs (75). Their immunomodulatory features, together with their tissue-trophic properties, make mesenchymal stem cells good candidates to treat IL-17 T-cell–mediated lung disease. Experimental work confirmed the inhibition of Th17, iNKT, and γδ T cells, and resulted in reduced tissue injury and enhanced tissue repair (76, 77). The few clinical trials performed demonstrated that this therapy is safe and feasible (78). However, its wide application in clinical practice is still far off.

Antibody- or DNA-based therapies.

An alternative might be cell blockade by monoclonal antibody therapy or DNA-based vaccination. Antibody therapies for the IL-17 T-cell phenotype can be specific or nonspecific. Nonspecific blockade includes antibodies against IL-2Rα, CD3ε, CD25, CD52, CD28, and TNF-α, which can have beneficial effects in the described phenotype by increasing Tregs and indirectly decreasing Th17 cells, like anti-IL2Rα (CD25; basiliximab) (17). Administration of LY2439821, an anti–IL-17 monoclonal antibody, has been described in rheumatoid arthritis and improved signs and symptoms of rheumatoid arthritis, without adverse events (79). Inhibitors of IL-21 and IL-22 have not yet reached the clinical setting (80, 81). Another option might be down-regulating IL-1β, IL-6, and IL-23, the Th17 inducer cytokines. A monoclonal antibody (ustekinumab) against p40 (a unit shared by IL-23 and IL-12) blocks Th1 and Th17 cells and was efficient in the treatment of psoriasis and Crohn's disease (82). Tocilizumab targets IL-6R and balances the Th17/Treg cell ratio toward Tregs and proved to be effective in treating rheumatoid arthritis (83). Likewise, blocking of IL-1R proved to be efficient (84). Overall, two considerations must be made. Most antibody therapies have not yet been tested in lung pathology, which is unique because of the lung's continuous exposure to innate triggers and pathogens. The risks of antibody therapies, such as acute anaphylaxis, serum sickness, and the generation of antibodies, must be kept in mind. In addition, there are numerous adverse effects of monoclonal antibodies that are related to their specific targets, including infections and cancer, autoimmune disease, and organ-specific adverse events such as cardiotoxicity. All these issues need consideration before antibody treatment can be introduced (85). Using DNA-based vaccinations for manipulating IL-17 T-cell responses might be an alternative. This approach can range from nonviral transfection (naked DNA or naked DNA loaded into liposomes) to viral transduction (DNA incorporated into a specific vector that targets the mucosal surface of the lung) (86). Although this approach may have great potential, it is even further away from clinical reality in the treatment of lung chronic lung disorders.

Nonspecific Blockade of the Innate Immune System

The best documented treatment for the neutrophil–IL-17 T-cell phenotype is macrolide therapy, which is moving into clinical practice to control airway neutrophilia in various pulmonary diseases such as diffuse panbronchiolitis, CF, asthma, COPD, and BOS after lung transplantation (87, 88). Within lung transplantation we described that the IL-17 T-cell–mediated neutrophilia phenotype can be reversed and prevented (40, 89). Work in progress demonstrated that, besides neutrophils, IL-17 T cells are decreased by azithromycin (49). Macrolide therapy is used at subclinical doses and therefore almost no side effects are observed. The only concern would be bacterial resistance, which we did not observe (89). Vitamin D therapy might have potential in controlling IL-17 T-cell–mediated lung diseases. Vitamin D is involved in cellular proliferation, differentiation, and apoptosis and the vitamin D receptor is omnipresent on immune cells (90). In vitro, vitamin D inhibits Th17 cells and promotes Tregs (90). Vitamin D deficiency is highly present in elderly patients and patients with COPD (91). Clinical trials that could prove the importance of vitamin D in chronic lung diseases are currently underway. Every medication capable of dampening the innate immune system, such as vitamin A, statins, and even probiotics, merits attention. Vitamin A (retinoic acid) down-regulates Th17 differentiation and activation (90). Retinoic acid, via its anti–Th17 cell activity, partially protects from and restores the lung function in rats with elastase-induced emphysema, indicating a role in COPD therapy. Retinoic acid produced by mucosal DCs regulates Treg and Th17 cell differentiation (90). Addition of retinoic acid enhances Treg conversion by inhibiting cytokines that interfere with conversion and by affecting the ability of these cytokines to inhibit Treg conversion (90). Determining the extent to which retinoic acid contributes to the treatment of IL-17 T-cell lung disorders merits attention. Statins directly down-regulate IL-6, IL-23, and RORC and promote Treg cells (92), and trials in multiple sclerosis and rheumatoid arthritis have shown beneficial effects (93, 94). In bronchial epithelial cells derived from human lung transplant recipients, statins proved to be effective in attenuating the release of neutrophilic and remodeling factors after IL-17 stimulation (45). Administration of probiotics demonstrated therapeutic potential in experimental inflammatory bowel disease, atopic dermatitis, and rheumatoid arthritis. Probiotics can up-regulate Tregs and down-regulate Th1, Th2, and Th17 cytokines (95).

In conclusion, in addition to azithromycin therapy, new treatment strategies are finding their way into the treatment of IL-17 T-cell–mediated lung disorders.

Th17 cells are the subject of great research interest because of their potential to induce pronounced neutrophilic inflammation, a common feature of many chronic (lung) inflammatory conditions. In this review we have also stressed the role of IL-17 sources besides Th17 cells. Whereas Th17 and Tc17 cells represent the adaptive immune system, γδT-17, NKT-17, and LTi-17 cells are the fast IL-17–producing members of the innate immune system. We reviewed a typical phenotype of neutrophilic inflammation induced by IL-17 T cells in chronic lung disorders. Recognizing this phenotype is crucial because it directs therapy. Macrolide therapy has already demonstrated great potential, but other agents are being explored as well. Further research is needed, including basic immunological research focusing on the interplay between the various subsets of IL-17 T cells. This review demonstrates that a multidisciplinary approach is crucial for optimal patient management and for a better understanding of the immunological basis of diseases.

The authors thank Prof. Geert M. Verleden for critically reviewing the manuscript.

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Correspondence and requests for reprints should be addressed to B. Vanaudenaerde, Ph.D., Katholieke Universiteit Leuven, Laboratory of Pneumology, Lung Transplantation Unit, 49 Herestraat, B-3000 Leuven, Belgium. E-mail:

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