Th17 T cells: Linking innate and adaptive immunity

Seminars in Immunology 19 (2007) 353–361

Review

Th17 T cells: Linking innate and adaptive immunity Brigitta Stockinger ∗ , Marc Veldhoen, Bruno Martin Division of Molecular Immunology, The MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK

Abstract While the cytokine IL-17 has been cloned and described more than 10 years ago [Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 1995;3(6):811–21; Kennedy J, Rossi DL, Zurawski SM, Vega Jr F, Kastelein RA, Wagner JL, et al. Mouse IL-17: a cytokine preferentially expressed by alpha beta TCR + CD4-CD8-T cells. J Interferon Cytokine Res 1996;16(8):611–7], it was only 2 years ago that IL-17 producing T cells have been classified as a new distinct CD4 T cell subset [Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005;6(11):1123–32] and only in 2006 the molecular mechanisms underlying their differentiation were identified [Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24(2):179–89; Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441(7090):235–8; Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006;441(7090):231–4]. Since then the literature on IL-17 producing cells has grown steadily and many reviews of the field are already outdated by the time they are published, a fate that no doubt will affect this review as well. In order to avoid too many repetitions we focus this review mainly on publications in 2006 and 2007 and refer to a number of reviews, which cover earlier aspects of Th17/IL-17 biology. © 2007 Elsevier Ltd. All rights reserved. Keywords: T cell differentiation; Th17; TGF␤; Cytokines; Autoimmunity; Innate immunity; Adaptive immunity

1. Differentiation of Th17 T cells: what it takes in vitro The independent discovery in three different labs of the differentiation factors for Th17 T cells, IL-6 and TGF␤, simplified in vitro analysis of this T cell subset substantially [4–6]. In addition, it provided rational explanations for observations in a number of pathological situations in vivo linking IL-17 and these two cytokines. The orphan receptor ROR␥t is the key lineage defining transcription factor for Th17 T cells [7] and downstream signalling for Th17 differentiation depends on activation of Stat3. The gp130-Stat3 pathway is essential for Th17 development and expression of ROR␥t [8–10] and deficiency in the suppressor of cytokine signalling Socs3 is a negative regulator of IL-6 and IL-23 signalling thereby constraining the generation of Th17 T cells [11]. Furthermore, it has been suggested that IL-21 acts downstream of IL-6 also involving Stat3 and thus amplifies Th17 generation [12–14]. These data account for

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the effects of IL-6 and IL-23 on downstream signalling pathways involved in Th17 differentiation, but no clear picture has emerged yet how TGF␤ signalling interfaces with Th17 differentiation. The perception that TGF␤ merely functions to dampen Th1 and Th2 differentiation, thus facilitating Th17 differentiation was borne out by the finding that culture of CD4 T cells in the presence of neutralizing antibodies to IFN␥ and IL-4 results in the emergence of IL-17 producing T cells [3]. However, these data preceded the identification of IL-6 and TGF␤ as differentiation factors and as we subsequently described, antibodies blocking Th1 and Th2 development will only allow Th17 differentiation in the presence of activated antigen presenting cells and the effect is lost upon addition of neutralizing anti-TGF␤ [4]. This clearly indicates that TGF␤ does more than simply block Th1 and Th2 differentiation. In this case the only source of TGF␤ could have been dendritic cells—blockade of IFN␥ and IL-4 in dendritic cell free cultures containing IL-6, TNF and IL-1, but no exogenous source of TGF␤ did not allow Th17 generation. Presumably antigen presenting cells produce low amounts of TGF␤ whatever the activation stimulus is, but the relative amounts of other cytokines, notably IL-12, will determine whether Th1, Th2

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or Th17 effector differentiation will occur. Important additional co-factors of Th17 differentiation are IL-1 and TNF. In fact IL1␣␤ double deficient mice as well as IL-1RI deficient mice have greatly reduced disease severity in EAE [15,16]. Although it is simple to generate Th17 T cells in vitro, provided one starts with a homogenous source of genuinely na¨ıve T cells, it is remarkably difficult to achieve this differentiation in the presence of contaminating pre-activated T cells or preactivated antigen presenting cells due to the strong inhibitory effects of IFN␥, IL-4 or IL-12 on this pathway [3,4]. More recently IL-2 has been suggested to inhibit Th17 differentiation. Since in vitro stimulation under conditions that polarize different subsets never leads to complete differentiation of all activated T cells, restimulation of Th17 containing cultures with IL-2 results in outgrowth of Th1 T cells and suppresses further expansion of Th17, whereas restimulation in the presence of IL-23 has the opposite effect [4]. However, IL-2 was suggested to have a direct inhibitory effect on Th17 differentiation via a Stat5 dependent pathway [17]. Nevertheless, we found that while IL-2 suppresses the expression of IL-17A, it does not affect expression of either IL-17F or the lineage transcription factor ROR␥t (manuscript in preparation). It is therefore unlikely that IL-2 prevents differentiation of the lineage, but it clearly affects expression of the cytokine IL-17A. This is an important caveat, which needs to be borne in mind as long as we depend on intracellular staining for IL-17A cytokine expression for identification of the lineage. The generation of reporter mice will be essential to overcome this problem and it seems the first reporter mice for IL-17F have been made and will probably be published before this review is due to appear. Given that immunologists tend to add IL-2 to their T cell cultures almost by impulse because it is required for Th1, Th2 or CD8 T cell cultures, it is not surprising that the degree of Th17 polarization documented – as measured by intracellular staining for IL-17A – varies substantially in the literature. This is especially the case in the human system were currently the assumption exists that TGF␤ is not required for Th17 differentiation because on the whole researchers failed to obtain good Th17 polarization with supposedly na¨ıve CD45RA positive CD4 T cells. It is likely that difficulties in obtaining primary Th17 differentiation from human CD4 T cells reflect a number of technical problems, not least insufficient purification of na¨ıve T cells. Since humans are continuously subjected to multiple infections unlike mice kept under pathogen free conditions, it is to be expected that there will be far more interference by inhibitory cytokines such as IFN␥, IL-4 or IL-12 on in vitro differentiation of superficially purified na¨ıve T cells. Given that the IL-17 family appear to be evolutionary ancient as is TGF␤ (reviewed in [18]), it is unlikely that humans would have evolved a drastically different strategy to generate Th17 T cells. The assumption that Th17 T cells in the human only develop from memory T cells in response to IL-23 on the other hand is clearly related to the issue of na¨ıve T cell purification. Human Th17 T cells preferentially express the chemokines CCR6 and CCR4 and purification of activated T cells on the basis of co-expression of these markers enriches for IL-17 producing T cells expressing the human ortholog of ROR␥t [19]. Interestingly, memory T cells specific

for recall antigens such as Candida albicans are exclusively contained in the CCR6/CCR4 positive subset that produces IL-17, whereas PPD or Mycobacterium tuberculosis specific T cells express other chemokine receptors and lack IL-17 production. 2. Th17 differentiation and function in vivo Given the multiple pitfalls seen in Th17 differentiation in vitro and in addition the inhibition produced by the autocrine T cell cytokine IL-2, which is invariably induced upon T cell activation it seems puzzling how a Th17 responses can ever get established in vivo. The cytokines driving Th17 differentiation in vitro are also crucial for their development in vivo. This is exemplified by the finding that IL-6 deficient mice fail to generate Th17 T cells and are protected against Th17 mediated diseases such as EAE or rheumatoid arthritis. Furthermore, mice with a T cell specific impairment of TGF␤ signalling due to transgenic expression of a dominant negative TGF␤ receptor II also do not develop Th17 T cells and are resistant to EAE [20]. However, it is presently unclear what the physiological conditions are that allow Th17 differentiation despite the presence of interference by pre-existing Th1 or Th2 cells or the inhibitory effect of IL-2 in vivo. It is likely that the answer lies in the local interaction of antigen presenting cells with na¨ıve T cells. While TGF␤ is ubiquitously produced by every cell in the body, local blockade of TGF␤ at the site of immunization rather than systemic blockade was most efficient at blocking the development of EAE. Thus, incorporating the neutralizing antibody in the antigen emulsion, was able to block the development of EAE, whereas systemic injection of anti-TGF␤ at this dose had no effect [20]. This suggests that TGF␤ production at the site of T–APC interaction is crucial for the development of Th17 T cells. Systemic injection of 10-fold higher antibody doses nevertheless did result in a 50% reduction of Th17 induction in the SKG mouse strain that is genetically prone to autoimmune arthritis due to a mutation in ZAP-70 that impairs thymic selection [21]. While this does not contradict the assumption that TGF␤ at the T cells–APC interphase is critical for Th17 differentiation, a recent study, using mice with T cell specific deletion of TGF␤, showed that T cell produced TGF␤ promoted Th17 differentiation and was indispensable for the induction of EAE [22]. This finding seems to contradict the notion that DC derived TGF␤ could drive Th17 differentiation. It is nevertheless possible that the interaction of APC with T cells under certain conditions drives mutual increase in TGF␤ production or its activation from the latent precursor. As far as the in vivo emergence of Th17 cells is concerned, the state of antigen presenting cells and local cytokine milieu are likely to be the key for their development. Clearly there are stimuli that result in modifying the response of antigen presenting cells. Activation of cell surface bound TGF␤ in a latent form on immature dendritic cells [23] may play a role in Th17 differentiation. Some pathogens or pathogen derived molecules such as Bordetella pertussis, M. tuberculosis, C. albicans or the fungal cell wall component zymosan promote IL-17 differentiation [20,24,25] and in the case of zymosan, increased production of IL-10 [26]

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and TGF␤ [27] concomitantly with reduced levels of IL-12 p35. Bordetella bronchiseptica was shown to modulate macrophage function, resulting in high levels of PGE2 secretion and was linked to increased production of IL-17 by CD4 T cells [28]. Induction of PGE2 by IL-17 was reported long before the definition of the Th17 subset [29]. IL-17 producing T cells play an important role in the re-call response to M. tuberculosis following vaccination. In the absence of IL-23 and IL-17 the expression of chemokines that serve to recruit protective IFN␥ producing T cells into the lung was impaired, suggesting an important coordinator function for IL-17 [30]. It therefore seems that Th17, via their interaction with the innate immune system may amplify and coordinate protective immune responses carried out by other subsets of CD4 T cells. Alterations in the ratio and type of cytokines that are produced in response to particular microbial stimuli are certain to underlie the in vivo induction of Th17 T cell differentiation. DC are stimulated by a variety of pattern recognition pathways that influence T cell differentiation. Dectin-1 engagement by ␤-glucan is important for control of fungal infections [31,32] and Syk–CARD9 coupled innate signalling pathways may promote DC activation to such infections independent of TLR [33]. Furthermore, the Nod-like receptor family member Nod1 contributes to the innate recognition of pathogen molecules such as peptidoglycans and in synergy with TLR signals primes Th17 responses [34]. Interestingly, non-haematopoietic lineage cells were required for the orchestration of Nod1 mediated signals, emphasizing again the crucial role of the local microenvironment in which responses are initiated. In this context it is important to consider that other IL-17 producers, notably ␥␦ T cells, may contribute the first line of defence [35,36] via their recruitment of neutrophils and that generation of Th17 could be a secondary step necessary if the innate immune system cannot cope. In addition to ␥␦ T cells, it was reported that a subset of NKT cells can produce IL-17 [37] and mRNA for IL-17 is detectable also in neutrophils [38]. This is an important fact to consider since frequently ELISA determination of IL-17 cytokine from unseparated cell populations is extrapolated to indicating the action of Th17 T cells, which may be a considerable overstatement. Furthermore, mRNA for IL-17 was detected in the intestinal tract of Rag deficient mice treated with anti-CD40 antibody although its cellular source remained unidentified [39]. Given the association of Th17 T cells with autoimmune disorders, it seems likely that the induction and duration of a Th17 T cell response has to be tightly controlled in order to prevent harmful immune pathology and autoimmunity. One puzzling feature in this context is the finding that Th17 T cells, which are difficult to detect in peripheral lymphoid organs of mice in clean animal facilities, nevertheless appear to be constitutively present (about 10% of CD4 T cells) in the lamina propria of the small intestine of apparently healthy mice. This was revealed by the analysis of mice in which the expression of ROR␥t, the lineage defining transcription factor for Th17, is reported by GFP [24]. This is particularly poignant in light of several reports that link production of IL-23 (and indirectly IL-17) with several models of intestinal inflammation [40–42].

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3. Th17 and Treg: what is the connection? Th17 and Treg development were suggested to be linked by their joint predilection for TGF␤ (reviewed in [43]). We initially detected Th17 differentiation in co-cultures of na¨ıve CD4 T cells and Treg and LPS activated DC [4], a condition under which the proliferation of the responder cells could not be suppressed by Treg anymore as previously reported [44]. However, what was overlooked at the time was that the presence of Treg still resulted in complete abrogation of IFN␥ and IL-2 secretion by responder cells. Treg could be replaced by TGF␤ and as little as 25 pg of this cytokine sufficed to drive Th17 differentiation. At the time we assumed that Treg had contributed TGF␤ as they are known to produce this cytokine or express it on the surface in its latent form [45] and some of their in vivo functions, e.g. suppression of Th1 mediated colitis, appear to depend on TGF␤ [46]. Furthermore, the possibility that Treg may modify the response of DC in a manner that supports TGF␤ secretion, similar to their ability to induce IL-10 in DC cannot be excluded [47]. However, it is clear that activated Foxp3 positive Treg produce sufficient TGF␤ in the absence of any APC to support Th17 generation and apparently can undergo self-induced Th17 differentiation [48]. In vitro activation of na¨ıve NOD T cells with ␤-cell peptide pulsed DC in the presence of TGF␤ supported their differentiation to Foxp3+ regulatory cells that not only inhibited T cell responses in vitro, but also suppressed ongoing diabetes upon adoptive transfer [49,50]. Whether or not the in vitro phenomenon of Treg generation from na¨ıve peripheral CD4 T cells by TGF␤ significantly contributes to the pool of Treg cells under physiological conditions in vivo remains unclear. Certainly the gut environment which is rich in TGF␤ is capable of supporting extrathymic Treg development directed by dendritic cells from the lamina propria and dependent on TGF␤ and retinoic acid [51,52] which suggests that retinoic acid is an important regulator between pro-inflammatory Th17 differentiation and anti-inflammatory Treg development [53]. It is not clear, however, whether such cells leave the intestinal tract and participate in the regulation of immune responses elsewhere. Mice with impaired TGF␤ signalling in T cells seem to have functional Treg, albeit other T cells cannot respond to their suppressive signals [54]. On the other hand, abrogation of TGF␤ production by T cells does abrogate the suppressive function of Treg in vivo, but not in vitro [22]. In addition, it might be important to consider the inverse relationship between IL-17A expression and Treg with regard to IL-2. This cytokine is an obligatory survival factor for Treg [55,56], whereas it inhibits the expression of IL-17A [17] even if it may not affect development of the Th17 lineage. One might wonder whether the presence of Treg in the vicinity of an incipient T cell response might favour the diversion to Th17 producing high levels of IL17A by virtue of their strong ability to soak up IL-2 [57,58]. In fact, increased induction of IL-17A producing T cells was observed in a model of T cell mediated systemic autoimmunity in IL-2 deficient mice [59]. This suggests that Treg may not suppress Th17 responses as effectively as they can suppress Th1 and Th2 responses and on the contrary might support production of highly pro-inflammatory IL-17A.

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4. Th17 make more than IL-17 Although currently the Th17 subset is linked to expression of the IL-17 cytokine, it is now clear that these cells make more than just IL-17. The other IL-17 family member IL-17F has not received as much attention as IL-17A mainly due to initial lack of reagents to measure IL-17F, but more data on its expression and role are expected to appear in the near future as well as IL17F reporter mice, which should greatly facilitate elucidation of its role in vivo. The phenotype of the IL-17A knockout mouse suggests that the major functions of IL-17A and IL-17F do not overlap unless IL-17F expression is also affected in this mouse; this has not been ascertained as yet. In addition to IL-17A and F, Th17 cells make IL-22, an IL-10 family member, originally defined as IL-10 related T cell derived inducible factor (IL-TIF [60]) which is co-expressed with IL-17 and was reported to be upregulated by IL-23 [61]. This would be a new function for IL-23 which seems reminiscent of the role of IL-18 in amplifying IFN␥ secretion by Th1 T cells [62]. IL-23 could also induce IL-22 production from ␥␦ T cells and CD8 T cells [63]. In contrast to the IL-17 receptor which is ubiquitously expressed, IL-22 receptor consisting of an IL-22R␣ chain and the IL-10R␤ chain [64] is not found on haematopoietic cells, but is highly expressed on peripheral tissues such as liver, pancreas, small intestine, colon, kidney and skin [65]. Numerous studies have linked IL-22 with pro-inflammatory functions such as dermal inflammation, psoriasis, rheumatoid arthritis, inflammatory bowel and Crohn’s disease [61,63,66–69]. A genome-wide association study showed a strong association between Crohn’s disease and the IL23R gene [70]. On the other hand, IL-22 induces the expression of antimicrobial proteins that are needed for defense against pathogens in the skin [65] and plays a protective role in experimental autoimmune myocarditis [71] and in a murine hepatitis model where neutralizing antibody to IL-22 worsened T cell mediated hepatitis and gene delivery of IL-22 was protective involving activation of Stat3 [72,73]. IL-22R can activate, via Stat3, an anti-inflammatory pathway indistinguishable from IL-10, leading to the suggestion that the IL-22 system generates anti-inflammatory responses in peripheral tissues as a counterbalance to excessive inflammation [74]. IL-22 induces lipopolysaccharide-binding protein (LBP) in hepatocytes and increased levels of this protein are detected in Crohn’s disease patients, suggesting that IL-22 may counteract systemic inflammation caused by LPS through its induction of LBP [75]. Thus, it is presently not clear whether increased production of IL22 in various inflammatory situations actually contributes to inflammation or constitutes a counter-regulatory mechanism. 5. Regulation of Th17 in autoimmunity Irrefutable evidence has now displaced Th1 cells as crucial mediators for autoimmune diseases resembled by mouse models such as autoimmune encephalomyelitis (EAE) or collagen induced arthritis (CIA). The last stronghold for a role of Th1 in autoimmune responses such as EAE, was the lack of susceptibility of T-bet deficient mice [76], since T-bet is the crucial

lineage defining transcription factor for Th1 cells. However, it has since become clear that T-bet has additional functions in dendritic cells [77,78] as well as a role in regulating transcription of the IL-23 receptor [79] which connect it with Th17 T cells. EAE, CIA and autoimmune myocarditis are directly linked with IL-17 production as absence or neutralization of this cytokine can block initiation of disease ([80,81] reviewed in [82]). It is still not entirely clear how stable the Th17 phenotype is due to the technical difficulty of obtaining 100% polarized cultures so that any deviation from a Th17 phenotype could be the results of secondary outgrowth of previously unpolarized cells. Thus, secondary cultures of Th17 polarized cells with IL-2 led to a strong increase in Th1 differentiation, which we attribute to secondary expansion of previously activated, but unpolarized T cells in these cultures. Even less is known about plasticity of these T cells in vivo, but it is clear that they are influenced by cytokines that have no role in their initial differentiation, but instead shape their effector profile or survival such as IL-23 and IL-18. Th17 T cells express IL-18 receptor (Veldhoen unpublished) and synergy between IL-23 and IL-18 was reported to increase IL-17 production in a Stat4 dependent manner [9]. IL-23 is strongly linked to autoimmune pathology and several recent reviews have focused on its role in Th17 biology and its suitability as a therapeutic target [83–85]. It remains unclear whether IL-23 is essential for the survival of Th17 T cells, but it has an important role in their functional capacity. Thus, mice infected with the gut pathogen Citrobacter rodentium fail to clear the infection in p19 (IL-23) deficient hosts although they induce a Th17 response [6]. In a mouse model of EAE in which disease was induced by injection of zymosan together with MOG the mice developed severe disease, but recovered after 3–4 weeks despite the presence of similar numbers of Th17 T cells in the spinal cord. Recovery correlated with reduced levels of IL-23 mRNA in DC isolated from draining lymph nodes as well as reduced levels of IL-17 cytokine produced by Th17 cells [20]. It therefore seems that IL-23 is needed to maintain production of the IL-17 cytokine. As long as we define the presence of the T cell subset Th17 by expression of its signature cytokine, it remains a possibility that Th17 T cells can persist in the absence of IL-23, but remain obscured because they are no longer producing IL-17A. This might well explain the relative ease with which Th17 cells can be revealed upon culturing activated T cells with IL-23. It is conceivable that a Th17 memory population can survive for long periods, but that it is unable to secrete IL-17A without an inflammatory stimulus that provides an IL-23 signal. In this way, such longlived memory cells would remain harmless because they do not secrete the cytokine that is instrumental in coordinating the immune response as well as the immune pathology associated with Th17 T cells. Any repeated inflammatory episode might then upregulate IL-17 again and if not cleared could lead to flare up of autoimmune pathology. Expression of the CCR6 chemokine receptor, like on human Th17 is also found on mouse Th17 T cells and the ligand CCL20 is upregulated on synovial tissue by IL-1, IL-17 and TNF (Hirota et al. manuscript submitted). Given that IL-17 upregulates IL-1, TNF and IL-6 in a positive feedback loop, it is conceivable that the downregulation of IL-17 production may suffice to dampen recruitment

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of further cells and interrupt the pro-inflammatory cascade that propagates autoimmune pathology. Expression of IL-23 seems essential both for a protective immune response as well as the development of autoimmune pathology. Theoretically this might limit the therapeutic benefits of strategies that target IL-23, but it remains to be tested whether its presence in host defence to a pathogen may be more limited in time and resolve in concert with clearance of the pathogen while only longterm chronic production of IL-23 may lead to development of autoimmune pathology. Targeting IL-23 instead of targeting the p40 subunit that is shared between IL-12 and IL-23 may be clinically advantageous with regard to treatment related infection (reviewed in [86]). SOCS3 is a negative regulator of Th17 differentiation, inhibiting Stat3 activation in response to IL-6 [87] as well as IL-23 [11]. The role of IL-18 in vivo is less clear, but interestingly IL-18 receptor plays an important role for autoimmune inflammation as mice deficient in IL-18 receptor expression, but not IL-18 cytokine are resistant to EAE induction. Although Th17 express IL-18 receptor, it was expression on antigen presenting cells rather than T cells that seemed crucial for this effect [88]. The fact that mice deficient in IL-18 were normally susceptible to EAE suggests an alternative ligand other than IL-18 for binding of this receptor. Interestingly, IL-18 receptor deficient antigen presenting cells expressed less IL-12/23 p40, but similar levels of IL-23p19 as wildtype APC. This could be a clue for the mechanistic basis of IL-18 receptor involvement. The expression of IL-12/23 p40 as a homodimer by DC is crucial for their migration into target sites as shown in a mycobacterial infection [89], where p40 deficiency reduces DC migration and can be overcome with exogenous p40 homodimers. Thus, it is possible that ligation of IL-18 receptor by another cytokine of the IL-1 family is involved in priming DC for migration to peripheral target tissue, providing a pro-inflammatory stimulus for continued IL-17 production. An intriguing feature of the Th17 response in highly inflammatory situations such as acute EAE is the co-expression of IL-17 and IFN␥. In our hands Th17 cells found in the spinal cord in the early stage of EAE development express IL-17 and not IFN␥, whereas the acute stage is characterized by a marked increase in double producers, which decrease again once the disease becomes chronic (unpublished observations and [7,20]). Considering the strong inhibitory effect of IFN␥ on in vitro differentiation of Th17 cells and the rarity of double producers seen in vitro, it is remarkable that the co-production of IL-17 and IFN␥ appears to be associated with increased pathogenicity, a feature that may also be important in unravelling the role of Th17 T cells in the gut. The role of Treg in Th17 mediated autoimmune disease seems to be compromised. Despite their presence in increased numbers in the spinal cord of mice with acute EAE they are unable to suppress the disease and their failure to suppress was attributed to the presence of IL-6 and TNF in CNS effector cells [90]. It is not clear however, that the source of IL-6 and TNF were T cells, as this was determined by ELISA of non-purified cell populations, rather than intracellular staining. Equally possible if not more likely is that the state of antigen presenting cells, such

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as DC in the spinal cord influences the suppressive capacity of Treg. Myeloid dendritic cells, migrated into the CNS from the periphery were shown to be responsible for priming new Th17 effector cells in situ due to their production of TGF␤, IL-6 and IL-23 [91], thus amplifying pathology. Activated Treg can be found in inflamed synovial tissue, yet are not able to suppress inflammation, which seems to be related to the presence of TNF [92,93]. Thus, it appears that Treg may be preferentially active against Th1 or Th2 mediated pathology, but helpless in the face of Th17 mediated responses. DC on the other hand may not only hold the key to activating Th17 pathology, but also play a key role in the negative regulation of Th17 mediated immune response. In this respect it is clearly important that the cytokine IL-27 secreted by DC was found to be a negative regulator of Th17 differentiation [94,95]. 6. Autoimmunity and infection The link between infections and autoimmunity has been described in many instances, but its mechanistic basis remains unclear (reviewed in [96]). It is naturally revealing that experimental induction of autoimmune disease in mouse models is inextricably linked with the use of complete Freunds adjuvant containing mycobacteria. In fact in most cases additional mycobacteria are added to the antigen emulsion. It has been known for some time that some pathogens, notably mycobacteria can stimulate IL-17 production [24,97] so that at least in animal models the connection between a response directed by particular pathogen derived molecules towards Th17 differentiation and the onset of autoimmunity is rather clear cut. In our hands DC exposed to zymosan strongly drive Th17 differentiation from na¨ıve CD4 T cells and the combination of zymosan with MOG peptide was sufficient to induce EAE [20]. Similarly, the addition of bacterial peptidoglycan to MOG peptide in incomplete Freund’s adjuvant (IFA), could induce EAE [98], and peptidoglycan is detectable in antigen presenting cells within the brain of multiple sclerosis patients [99]. Furthermore, pertussis toxin, which is a major virulence factor of B. pertussis, promotes secretion of IL-6 and inhibits IL-2mRNA transcription, thereby facilitating Th17 differentiation [100]. The concerted action of genetic and environmental factors in the development of autoimmune disease was highlighted in SKG mice, which spontaneously develop Th17 T cells that cause arthritis in conventional, but not SPF mouse facilities [21]. Zymosan, a crude yeast cell wall extract containing fungal ␤-glucans that interact with their receptor Dectin-1 was previously shown to severe chronic arthritis in this strain [31]. It will naturally be impossible to formally establish such causal links in human autoimmune conditions, but the involvement of Th17 cells in many autoimmune conditions makes connections with certain infections highly likely. It is worth pointing out, however, that Th17 cannot be held responsible for all autoimmune conditions. For instance mice with disabled TGF␤ signalling in T cells which precludes the differentiation of Th17 T cells, develop hyperactive Th1 and Th2 responses that cannot be curbed by TGF␤. Mice expressing dominant negative TGF␤RII as transgene under control of the CD4 promoter

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Fig. 1. Sequential stages of IL-17 mediated immune responses.

develop autoimmune-like symptoms such as for instance biliary cirrhosis [101], but spontaneous effector differentiation occurs quite late if mice are kept in a clean animal house, which indicates that the block in TGF␤ signalling is not absolute [102]. In contrast, complete abrogation of TGF␤ signalling by deletion of the receptor results in severe early onset autoimmune disease with multiorgan infiltration and 100% mortality by 3 weeks of age [103,104]. Nevertheless, development of regulatory T cells is normal and the fatal disease cannot solely be ascribed to dysfunction of Treg, but rather seems to be caused by a cell-intrinsic failure of TGF␤ mediated control in T cells reactive to environmental stimuli. 7. Conclusions The Th17 T cell subset has risen to prominence rapidly during the last 2 years and new discoveries regarding their influence in the immune system are accumulating rapidly. Many previously unresolved questions may finally be clarified by taking into account the functional activities of this T cell subset. Given that their signature cytokine IL-17A can be contributed by a variety of other cell types, it is conceivable that the system evolved primarily from an innate IL-17 mediated response, which may in many cases suffice to clear an invading pathogen. If this fails, the presence of TGF␤ as a component associated with cellular stress, injury and inflammation together with IL-6, IL-1 and TNF secreted by activated antigen presenting cells would provide the conditions for differentiation of Th17 T cells as a second layer of immune defense. We hypothesize that autoimmunity only arises if this additional immune force fails to clear the pathogen, resulting in chronic inflammation that would provide the conditions for exacerbation into autoimmune inflammation (Fig. 1). Many questions still remain to be solved, but considering the speed with which Th17 research progresses one can expect answers before too long.

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