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NDT Advance Access originally published online on November 28, 2007
Nephrology Dialysis Transplantation 2008 23(3):816-819; doi:10.1093/ndt/gfm800
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Th17 cells: a third subset of CD4+ T effector cells involved in organ-specific autoimmunity

Christian Kurts

Institute of Molecular Medicine and Experimental Immunology (IMMEI), Friedrich-Wilhelms-Universität, 53105 Bonn, Germany

Christian Kurts, Institute of Molecular Medicine and Experimental Immunology (IMMEI), Friedrich-Wilhelms-Universität, 53105 Bonn, Germany. Tel: +49-228-287-11031; Fax: +49-228-287-11052; E-mail: ckurts{at}web.de

Keywords: autoimmunity; cytokines; dendritic cells; interleukin 17; T cells



   The Th1/Th2 paradigm in immunity
Top
 The Th1/Th2 paradigm in...
A novel CD4+ T-effector-cell...
 Differentiation and molecular...
 Role of Th17 cells...
 Current concepts on the...
 Concluding remarks
 References
 
CD4+ T helper cells orchestrate and regulate adaptive immune responses. From a functional perspective, they can be classified into CD4+ regulatory T cells (Treg) that show immunosuppressive activity and into CD4+ T effector cells that combat infectious pathogens. An important aspect of antimicrobial activity is the choice of the appropriate weaponry suitable to combat a particular class of pathogens. This selection is facilitated by distinct subsets of CD4+ T effector cells that produce cytokines to which the respective immune effectors are responsive. Thus, type 1 CD4+ T effector cells (Th1 cells) secrete IFN{gamma} and TNF{alpha} to recruit macrophages for combating bacterial infections [27], or IL-2 to license cytotoxic CD8+ T cells for killing virally infected cells [8]. They also stimulate B cells to produce opsonizing and neutralizing antibodies that intercept circulating pathogens. In contrast, Th2 cells secrete IL-4, IL-5 and IL-13 to recruit a different class of immune effectors, which is aimed against parasites such as immunoglobulins of the IgE subtype, eosinophils and mast cells, which bind IgE [37]. In this fashion, the immune system avoids collateral tissue damage by immune effectors whose weapons are unsuitable against a particular infectious challenge.

The differentiation of antigen-unexperienced ‘naïve’ T cells into Th1 or Th2 cells occurs during their activation (‘priming’), which is facilitated by dendritic cells (DC). These professional antigen-presenting cells possess pattern-recognition receptors by which they can sense the quality of an infectious challenge. For example, toll-like receptors detect the presence of lipopolysaccharides or of bacterial or viral DNA, resulting in IL-12 production, which induces Th1 differentiation by engaging transcription factors such as T-bet, STAT1 or STAT4 within the T cells (Figure 1). Th2 differentiation is caused by IL-4-mediated engagement of the transcription factors STAT6 and GATA-3, but the molecular patterns and DC receptors detecting parasite infections are not known. In the absence of pathogen-associated molecular patterns, DCs can induce Tregs, for example by secreting TGF-β, which upregulates the transcription factor FoxP3 characteristic of some Treg subsets [12,20] (Figure 1).


Figure 1
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  		Fig. 1 Differentiation and regulation of CD4+ T-cell subsets.

 


   A novel CD4+ T-effector-cell subset distinct from Th1 and Th2
Top
 The Th1/Th2 paradigm in...
 A novel CD4+ T-effector-cell...
Differentiation and molecular...
 Role of Th17 cells...
 Current concepts on the...
 Concluding remarks
 References
 
The Th1/Th2 paradigm was discovered more than 20 years ago in seminal studies by Robert Coffman and Tim Mosman [27,28] and has shaped our view not only of anti-infectious immunity, but also of immune-mediated diseases. Although it has long been known that the Th1/Th2 paradigm is not an absolute dichotomy, this concept has been enormously useful in the past and is still used to date. Recent work, however, has revealed a distinct novel class of CD4+ T effector cells that do not fall into either category. As the term Th3 is already in use for one of the subsets of regulatory T cells, these cells have been named Th17 cells [3,6,10,14,32], due to their characteristic production of proinflammatory molecules of the IL-17 family. This cytokine family comprises the founding member IL-17 (also termed IL-17A), IL-17B, IL-17C, IL-17D, IL-17E (=IL-25) and IL-17F [18,43]. IL-17A very potently promotes tissue inflammation by inducing proinflammatory cytokines and chemokines, which attract and activate granulocytes and macrophages [18,39,43].

Th17 cells not only differ from Th1 and Th2 cells by the cytokines they produce, but also by the mechanisms that drive their differentiation [7,38,43]. Intriguingly, they seem to be related to FoxP3+ Tregs and differentiation of these two cell types seems to be regulated reciprocally, at least in mice [6]. Th17 cells are characterized by the activity of distinct transcription factors, in particular ROR{gamma}t and STAT3 [7,15,43] (Figure 1), which initiate a characteristic molecular transcription program. Formal proof for a third differentiation lineage came from mice lacking Th1- or Th2-specific transcription factors, whose CD4+ T cells were still able to differentiate into Th17 cells under appropriate conditions [14]. Finally, certain models of autoimmune diseases, such as experimental autoimmune encephalitis (EAE), a murine model of multiple sclerosis, are mediated mostly by Th17 cells [6,10,36]. Taken together, these lines of evidence supported the conclusion that Th17 cells represent a unique CD4+ T effector cell type, and are distinct from Th1 and Th2 cells.



   Differentiation and molecular regulation of Th17 cells
Top
 The Th1/Th2 paradigm in...
 A novel CD4+ T-effector-cell...
 Differentiation and molecular...
Role of Th17 cells...
 Current concepts on the...
 Concluding remarks
 References
 
The dependence of EAE and collagen-induced arthritis on the IL-12-family member IL-23, instead of IL-12 itself [10,30] was one of the first hints that molecular mechanisms distinct from classical Th1 differentiation can result in cell-mediated autoimmunity. As DCs can produce IL-23 as well as IL-12, it was initially thought that IL-23 represents an alternative Th1 inducer. Later it was found that IL-23 maintains a distinct CD4+ T- effector subset, which we now know as Th17 cells, and that IL-23 in fact is responsible for their maintenance and survival [42,46]. Instead, murine Th17 cells differentiate under the combined influence of IL-6 and TGF-β during T-cell priming, which engage the transcription factors ROR{gamma}t, STAT3 and IRF-4 [6,9,15,25,26,46] (Figure 1). This discovery revealed a further dichotomy in T-cell differentiation that reciprocally linked Tregs with Th17 cells. The presence of IL-6 diverts differentiation of suppressive Tregs towards generation of highly proinflammatory Th17 cells. This induction mechanism may explain why Th17 cells are so prevalent in autoimmunity: when DCs present autoantigens to induce Tregs, the inappropriate presence of IL-6, resulting for example from inflammation or bystander infections, may cause maldifferentiation towards autoreactive Th17 cells, at least in the mouse. In contrast, human in vitro Th17-cell differentiation did not require TGF-β. Instead, IL-1 was shown to synergize with IL-6 in Th17-cell generation [1,44].

Several further factors were subsequently identified to regulate Th17 cells. IL-21 and IL-23 could replace IL-6 and induce Th17 cells via transcription factors ROR{gamma}t and STAT3 [7,19,46] (Figure 1), suggesting that these two cytokines acted downstream of IL-6. Negative regulators of Th17 cells include IL-25 (=IL-17E) [17] and IL-27 [4]. Also IL-2 signalling via STAT5, Th2 induction via IL4 and Th1 induction via IFN{gamma} inhibit Th17 polarization [23] (Figure 1).



   Role of Th17 cells in autoimmunity
Top
 The Th1/Th2 paradigm in...
 A novel CD4+ T-effector-cell...
 Differentiation and molecular...
 Role of Th17 cells...
Current concepts on the...
 Concluding remarks
 References
 
Increased IL-17 levels have been detected in patients with various autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, inflammatory colitis and rheumatoid arthritis 7. Its function of inducing additional proinflammatory cytokines and chemokines suggested a proinflammatory role in these conditions. In rheumatoid arthritis, its ability to induce matrix metalloproteases and stimulate osteoclasts may result in cartilage and bone destruction [18,43]. These clinical associations are supported by experimental models in mice. Genetic or antibody-mediated incapacitation of IL-17 or Th17 cells protected against adjuvant-induced arthritis, EAE and in an autoimmune uveitis model [4,6,10,25,30,31]. Th17 cells also promoted inflammatory colitis [5,11]. Recently, retinoic acid has been shown to completely abolish the ability of IL-6 to divert Treg induction towards Th17 cells in vivo, resulting in attenuation of colitis [29]. These findings established the role of Th17 cells in several models of immune-mediated diseases that had previously been ascribed to Th1 cells. In contrast, IL17 and thus possibly Th17 cells were protective in a Th2-dependent asthma model [34].



   Current concepts on the role of Th17 cells in immunity
Top
 The Th1/Th2 paradigm in...
 A novel CD4+ T-effector-cell...
 Differentiation and molecular...
 Role of Th17 cells...
 Current concepts on the...
Concluding remarks
 References
 
Why should nature permit proinflammatory cytokines to convert protective Treg into autoreactive T cells? Conceivably, Th17 cells did not evolve to induce autoimmunity. Thus, it has been proposed that Th17 cells are targeted against distinct classes of infectious pathogens, namely extracellular bacteria, whereas the main function of Th1 cells is seen in the defence against intracellular pathogens [39]. Indeed, Th17 cells have been shown to participate in the defence against gram-negative Citrobacter rodentium [26] and Klebsiella pneumoniae [13]. IL-17 itself is highly pro-inflammatory and induces expression of other inflammatory cytokines (e.g. IL-6 and TNF{alpha}) and chemokines (e.g. CCL2/MCP-1, CXCL1/KC, and CXCL2/MIP-2, a mouse homolog of IL-8) and of matrix metalloproteases important in facilitating the tissue entry of attracted leukocytes. IL-17 also mediates recruitment, activation and proliferation of neutrophilic granulocytes [27], the most crucial cellular weapon of the innate immune system against bacteria. Although neutrophils function well without T cells, Th17 memory cells, nevertheless, may improve their attraction and response during re-infection [2]. The claim that IL-17-deficient mice were not severely compromised in antibacterial defence against some pathogens does not argue against this hypothesis, because alternative recruitment mechanism may substitute for the genetic loss of IL-17. As currently available studies have been performed with mice deficient for only one of the IL-17 subforms, it remains possible that other members of the IL-17 family can act as backup inducers.

Recent evidence supports a role of Th17 cells also in the defence against fungi and parasites. Recognition of Candida albicans and Pneumocystis carinii can occur via dectin-1, a pattern-recognition receptor expressed by DCs [33,40]. Signalling via dectin-1 can result in Th17-cell generation directed against these pathogens [24]. Vaccination-induced Th17 cells were shown to mediate some protection against Mycobacterium tuberculosis [16]. Memory Th17 cells isolated from humans were found to be directed against this pathogen and against C. albicans [2], further supporting a selective role of Th17 cells against distinct pathogen classes.

Finally, IL-23- and IL-17-dependent chronic inflammation has recently been implicated in cancerogenesis [22]. These cytokines were increased in human tumours and IL-23 deficiency was protective in murine tumour models. The underlying mechanisms, however, remain to be elucidated.



   Concluding remarks
Top
 The Th1/Th2 paradigm in...
 A novel CD4+ T-effector-cell...
 Differentiation and molecular...
 Role of Th17 cells...
 Current concepts on the...
 Concluding remarks
References
 
The recent discovery of Th17 cells as a third type of effector T cells has added a further layer of complexity to our understanding of T-cell differentiation. On the other hand, we have learned about a new pro-inflammatory mechanism that appears to be centrally involved in distinct types of tissue-specific autoimmunity, infection and cancer. The eruption of numerous studies published in the leading scientific journals (see the Reference list) highlights that time was ripe for an overhaul of the Th1/Th2 paradigm that served immunological research so long and so well. Although the exact role of Th17 cells in anti-infectious immunity is far from being understood, there is evidence that these cells may contribute to the defence against bacterial, protozoal and fungal pathogens [24] that were not really covered by the Th1/Th2 theory.

In the field of immune-mediated diseases, the Th17-extended concept offers answers to long-known discrepancies resulting from the Th1/Th2 paradigm. Thus, it has been difficult to understand why inhibition of TNF{alpha} or IFN{gamma} was beneficial in rheumatoid arthritis, but detrimental in multiple sclerosis [36] (resulting even in a warning of the US Food and Drug Administration about the potential for worsening demyelinating disorders such as MS), although both diseases were viewed as Th1-dependent delayed type hypersensitivity. The involvement of Th17 cells can explain why targeting Th1 mechanisms was counterproductive. Furthermore, the breakthrough that TNF{alpha} blockade represents in treatment of rheumatoid arthritis and Crohn's disease may partially be due also to inhibiting Th-17 cells, which also produce some TNF{alpha}. The effectivity of IL-6-targeting therapies in rheumatoid arthritis [35,45] may be explained by mechanistic knowledge on the induction of Th17 cells.

However, despite the abundance of recent publications on Th17 cells in autoimmunity, one must not dismiss previous data demonstrating the role of Th1 cells in autoimmune diseases such as type 1 diabetes or crescentic glomerulonephritis [21,41]. Since Th1 and Th17 cells appear to cooperate in anti-infectious immunity [7,26,39], it appears conceivable that these cell types might liaise also in organ-specific autoimmunity with varying contributions of either subset. In kidney disease, the role of Th17 cells is completely unresolved, but undoubtedly will be addressed in the near future.

A further open question pertains to the regulation of human Th17 cells. Very recent findings showed that their differentiation required cooperation of IL-6 with IL-1, but not with TGF-β [1,44], questioning whether the notion of compromised TGF-β-mediated Treg induction as the cause of Th17 generation [7] is valid in humans. Finally, the nature of the pathogen-associated patterns driving Th17 development awaits elucidation.

It can be expected that the Th1/Th2/Th17 trinity will undergo further modifications, as immunologists resolve the mechanistic details underlying CD4+ T-effector-cell polarization, possibly resulting in an even more intricate picture. Nevertheless, the effort will be worthwhile as it promises new avenues for the development of specific therapies against immune-mediated diseases associated with less immuno-suppressive side effects.



   Acknowledgments
 
The author thanks Professor Dr Ari Waisman, Mainz, Germany, and Professor Dr Hans-Willi Mittrücker, Hamburg, Germany, for helpful discussions, and acknowledges support by the Studienstiftung des deutschen Volkes and the Deutsche Forschungsgemeinschaft (DFG), in particular the Sonderforschungsbereich (SFB) 704 and the Klinische Forschergruppe 155.

Conflict of interest statement. None declared.



   References
Top
 The Th1/Th2 paradigm in...
 A novel CD4+ T-effector-cell...
 Differentiation and molecular...
 Role of Th17 cells...
 Current concepts on the...
 Concluding remarks
 References
 

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Received for publication: 21. 9.07
Accepted in revised form: 15.10.07


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