Th17 cells in central nervous system autoimmunity.

YEXNR-11682; No. of pages: 10; 4C: Experimental Neurology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Experimental Neurology

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Review

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Th17 cells in central nervous system autoimmunity

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Christopher Sie a, Thomas Korn a,b,⁎, Meike Mitsdoerffer a,b,⁎

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Article history: Received 12 January 2014 Revised 12 March 2014 Accepted 19 March 2014 Available online xxxx

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Keywords: Multiple sclerosis Experimental autoimmune encephalomyelitis Th17 cells

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Multiple sclerosis (MS) is the most important autoimmune disease of the central nervous system (CNS). Its animal model experimental autoimmune encephalomyelitis (EAE) has been instrumental in defining the features of the novel T helper cell subset Th17. Conversely, the broad characterization of Th17 immune responses has substantially advanced our understanding of organ-specific autoimmunity and inspired almost a decade of immunological research. Here, we review the current knowledge on Th17 cells and their contribution to the immunopathology in EAE and MS, covering recent proceedings in the induction, modulation and effector mechanisms of this versatile T lymphocyte subset. In particular, we discuss the emerging role of mucosal immunity in the regulation of Th17 cells and CNS autoimmunity, the accumulating evidence for extensive plasticity in the Th17 subset, and their molecular mode of action in promoting this debilitating disease. © 2014 Published by Elsevier Inc.

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Introduction . . . . . . . . . . . . . . . . . . . Induction of Th17 cells . . . . . . . . . . . . . . Role of mucosal tissues in the induction of Th17 cells Trafficking of Th17 to CNS tissues . . . . . . . . . Plasticity of Th17 cells . . . . . . . . . . . . . . Th17 effector functions . . . . . . . . . . . . . . Regulation of Th17 responses . . . . . . . . . . . Th17 cells in multiple sclerosis . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .

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Introduction

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Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). Decades of research have established the hallmark that CNS-infiltrating T lymphocytes are among the major mediators of this debilitating disease in many experimental settings (Fletcher et al., 2010) and recent genome-wide association studies (GWAS) strongly support the notion that pathways in T cell activation

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Klinikum rechts der Isar, Technische Universität München, Department of Neurology, Ismaninger Str. 22, 81675 Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

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⁎ Corresponding authors at: Klinikum rechts der Isar, Department of Neurology, Ismaninger Str. 22, 81675 Munich, Germany. Fax: +49 89 4140 4675. E-mail addresses: [email protected] (T. Korn), [email protected] (M. Mitsdoerffer).

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and differentiation are relevant to the human pathology (Sawcer et al., 2011). A large body of evidence for the role of T cells in CNS autoimmunity comes from studies in rodent models of MS, with experimental autoimmune encephalomyelitis (EAE) being the most prominent approach for more than 70 years (Gold et al., 2006; Rangachari and Kuchroo, 2013; Zamvil and Steinman, 1990). In its classical induction regime, susceptible mouse strains are immunized by subcutaneous injection of CNS antigen emulsified in Complete Freund's Adjuvant (CFA). T lymphocytes primed in the peripheral compartment eventually infiltrate into the CNS. Importantly, EAE can also be induced passively by transferring autoaggressive CD4+ T lymphocytes into naïve recipients (Ben-Nun et al., 1981; Schluesener and Wekerle, 1985), highlighting the significance of T cells as mediators of the disease.

http://dx.doi.org/10.1016/j.expneurol.2014.03.009 0014-4886/© 2014 Published by Elsevier Inc.

Please cite this article as: Sie, C., et al., Th17 cells in central nervous system autoimmunity, Exp. Neurol. (2014), http://dx.doi.org/10.1016/ j.expneurol.2014.03.009

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Role of mucosal tissues in the induction of Th17 cells

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The cytokine milieu provided by antigen-presenting and bystander cells during T cell priming is dominant over other signals including antigen dose and costimulatory molecules in the commitment of naïve T cells to distinct T helper cell subsets. Emulating this microenvironment by stimulating T cells in vitro in the presence of exogenous cytokines has been instrumental in defining the molecular cues for T cell differentiation and in identifying core features of many T cell subsets. While the cytokine IL-23 was initially considered a differentiation factor for Th17 cells (Langrish et al., 2005), its capacity to induce IL-17 in naïve T cells was virtually absent and indeed, the IL-23R is not expressed on naïve T lymphocytes (Parham et al., 2002). By serendipity, it was found that the combination of TGFβ1 and IL-6 could drive the generation of Th17 cells and their expression of IL23R (Bettelli et al., 2006; Mangan et al., 2006; Veldhoen et al., 2006), a process that was amplified by the auto- and paracrine effect of IL-21, produced by Th17 cells themselves (Korn et al., 2007; Nurieva et al., 2007; Zhou et al., 2007). Th17 cells express IL-23R and IL-23 is paramount to the pathological function of CD4+ T helper cells which has been shown in many paradigms of T cell mediated inflammatory diseases (Croxford et al.,

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Induction of Th17 cells

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In the past few years, mucosal tissues and their local immune compartments, i.e. mucosa-associated lymphoid tissues (MALT), have received a special attention with regard to their influence on T cell immunity. Mucosal surfaces of the gut and lung are in constant interaction with a plethora of microbiota, pathogens and environmental factors. Therefore, they are of dual interest for MS and hence EAE pathology: first, they provide a means to explain the enigmatic environmental component in MS etiology and relapse triggering. Second, if there is a phase in which T cell responses are naturally modulated in these compartments, this opens a therapeutic window for pharmaceutical intervention by oral or aerosol medication. The lung mucosa is continuously exposed to environmental influences and has only recently been implicated in CNS autoimmunity. Odoardi et al. (2012) used an adoptive transfer model of EAE in rats to track myelin-specific, GFP+ T cells on their way to the central nervous system (Odoardi et al., 2012). Surprisingly, these encephalitogenic T cells did not only briefly pass through the lung's capillary network upon intravenous transfer but penetrated deep into the parenchyma, specifically homing to bronchus-associated lymphoid tissues (BALT) as well as bronchial structures. Here, they resided for several hours, actively scanning the mucosal surface of the bronchiolar lumen, before continuing into the periphery and infiltrating the CNS. Importantly, in addition to these observations from passive EAE induction regimes with T cells pre-activated ex vivo, bronchiole- and BALT-associated T cells were also found in actively immunized animals that had previously received resting GFP+ T cells. While the cultured memory T lymphocytes used in this model are known to have a mixed phenotype of IL-17/IFN-γ double producers (Bartholomäus et al., 2009), their intriguing accumulation and behavior in pulmonary structures could allude to a general scheme in activated T cells. However, whether this holds true for Th17 cells in mice and, more importantly, men remains to be discovered. For the gastrointestinal tract, a number of studies have implicated microbiota and nutritional factors in the modulation of Th17 responses and CNS autoimmunity (Berer and Krishnamoorthy, 2012). Th17 cells are abundant in the gut-associated lymphoid tissue (GALT) of mice colonized under normal, specific-pathogen free (SPF) conditions (Ivanov et al., 2006). However, mice treated with antibiotics (Ivanov et al., 2008) or hosted in completely pathogen-free environments failed to generate Th17 cells in the lamina propria, a feature that could be restored by re-colonizing the mice with specific commensal species, notably segmented filamentous bacteria (SFB) among others (GaboriauRouthiau et al., 2009; Ivanov et al., 2008, 2009). A possible mediator of this effect was commensal-derived adenosine triphosphate that induced the production of the Th17 differentiating cytokines IL-6 and IL-23 in cells of the lamina propria (Atarashi et al., 2008). Given their strong influence on local Th17 cells in the GALT, the impact of intestinal microbiota on Th17-driven diseases, notably EAE, was

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2012; McGeachy et al., 2009). It remains to be determined whether other subsets of T helper cells are also IL-23R positive. However, in contrast to Th17 cells, Th1 cells induced with IL-12 do not express IL-23R. An alternative way to induce Th17 cells in vitro was reported to occur in the presence of IL-1β (and independently of TGF-β). In fact, IL-1β together with IL-6 and IL-23 were described to induce a “pathogenic” subset of Th17 cells that in addition to ROR-γt also expressed T-bet and lacks IL-10 production (Ghoreschi et al., 2010). These findings have spurred the concept of different “flavors” of Th17 cells (Lee et al., 2012). It is well possible that different Th17 phenotypes are defined by the biological niche in which they are raised. It was found that CD103− dendritic cells (DCs) could prime Th17 cells independently of IL-6 in the spleen while IL-6 was critical for the induction of Th17 cells in skin and mucosa, where regulating CD103+ DCs that produced large amounts of TGFβ and retinoic acid dictated the requirement for IL-6 in Th17 priming (Hu et al., 2011).

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A key concept in our understanding of T cell biology is that the outcome of an unfolding adaptive immune response is largely defined by the phenotype of its constituting T helper (Th) cells. This in turn is determined by the microenvironmental signals integrated in naïve T cells during their initial encounter with a cognate antigen in a sequence of events subsumed as T cell priming. In the course of this process, T helper cells were originally believed to commit to one of two possible and mutually exclusive states of differentiation, coined Th1 and Th2 in a seminal paper by Mosmann et al. (1986). These two subsets were distinguished by means of their signature cytokine secretion, i.e. IFN-γ and IL-4 for Th1 and Th2 cells, respectively. Given the inflammatory nature of Th1 cytokines and their presence in MS lesions (Traugott and Lebon, 1988a, 1988b), Th1 cells were considered to solely drive the disease pathology in EAE. Initially, this concept was supported by the fact that gene targeted deletion of the p40 subunit of IL-12, a major Th1 differentiation factor, prevented the onset of EAE (Segal et al., 1998). However, other studies revealed that mice with genetic ablation of the Th1 signature cytokine IFN-γ (Ferber et al., 1996) or its receptor (Willenborg et al., 1996) as well as the IL12 subunit p35 (Becher et al., 2002; Gran et al., 2002) or its receptor IL-12Rβ2 (Zhang et al., 2003) were not only still susceptible to EAE but in some cases even presented with exacerbated rather than alleviated disease course. Therefore, the original Th1 paradigm could not exclusively account for the T cell driven EAE pathology observed in mice. The key to reconciling the concept of distinct T helper subsets with experimental evidence came with the notion that mice devoid of IL-23, a cytokine that shares the p40 subunit with IL-12 but constitutes a distinct molecule using p19 rather than p35 (Oppmann et al., 2000), were completely resistant to EAE (Cua et al., 2003). Prominently expanding the long standing dichotomy of Th1 and Th2 cells, it was then realized that IL-23 is implicated in the maintenance of a novel T cell subset, identified by its signature cytokine IL-17 as Th17 cells (Harrington et al., 2005; Langrish et al., 2005). Following this important discovery, it was soon appreciated that many organ-specific autoimmune diseases were not, as previously perceived, solely driven by Th1 cells but could also exhibit a relevant, if not decisive contribution of Th17 cells (Dardalhon et al., 2008). Here, we review the current knowledge on Th17 cells with a special focus on their role in CNS autoimmunity. While accumulating evidence suggests that T cell phenotypes are not limited to set profiles but can also exhibit a considerable degree of plasticity (Hirahara et al., 2013), the given Th nomenclature remains to provide a valuable conceptual framework that will be used throughout this review, bearing in mind that the described subsets likely represent only limiting cases of a highly dynamic system.

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of the gut and even more so the complete absence of microbiota in germ-free mice entails a severe disturbance of the whole immune system, producing extreme effects in EAE models that are not reflective of the human situation. From a mechanistic point of view, one of the important control elements for integrating these environmental signals directly within T cells is the aryl-hydrocarbon receptor (AhR). It is expressed in both Th17 and regulatory T cells, and different AhR-ligands can either enhance (Quintana et al., 2008; Veldhoen et al., 2008) or suppress Th17 induction (Quintana et al., 2008), thereby modulating the disease intensity of EAE. While environmental toxins can be a source of AhR ligands, they can also be derived from natural tryptophan metabolites of intestinal microbiota (Perdew and Babbs, 1991). Importantly, these bacteria-derived ligands as well as other immunogenic components can also enter the circulation (Henao-Mejia et al., 2012; Wikoff et al., 2009), potentially offering a way to reach and influence Th17 cells in extra-intestinal immune compartments (see also Fig. 1). The most recent evidence for the impact of mucosal immunity and nutrition comes from two studies that suggested dietary salt as a major factor in both Th17 induction and EAE pathology (Kleinewietfeld et al., 2013; Wu et al., 2013). These groups discovered that the presence

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addressed by several groups. In active immunization regimes, initial reports suggested no change in EAE severity in germ-free mice (Lampropoulou et al., 2008) whereas a substantial alleviation of EAE symptoms was reported by another group (Lee et al., 2011). In the latter study, EAE susceptibility could be restored by re-colonization with SFB. Conversely, other distinct commensal species (Ochoa-Repáraz et al., 2010) as well as certain probiotics (Lavasani et al., 2010) were also found to be protective in actively induced EAE. Recently, Berer and colleagues have highlighted the relevance of gut microbiota in spontaneous models of EAE (Berer et al., 2011). The disease incidence in their MOG-specific TCR transgenic mice varied substantially between different housing facilities, prompting a study to compare entirely germ-free with SPF-housed mice. While the latter had an 80% EAE incidence, those mice without intestinal microbiota were virtually resistant to disease development. Importantly, this protection could be reversed by re-colonization with gut bacteria from SPF mice even after 12 weeks of germ-free housing, whereas inoculation with SFB alone was not sufficient. The sum of these data provides strong circumstantial evidence for a potential modulation of the propensity to develop CNS autoimmunity by intestinal microbiota. However, despite diligent controls in these studies, it cannot be ruled out that a mono-colonization

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Fig. 1. Scenarios for Th17 cell modulation by the intestinal mucosa. Microbiota of the gut (lower panel) do not usually enter extra-intestinal, secondary lymphatic organs (SLO, medium panel) or even the CNS (top panel) to readily interfere with Th17 cells. Likewise, dietary salt does not dramatically raise sodium blood levels. Hence, the reported influence on encephalitogenic lymphocytes likely is exerted either directly within the mucosa associated lymphoid tissue or through intermediate effects. (a) T cells are modulated by various mechanisms within the lamina propria, thereby potentially committing to the Th17 phenotype. Nutritional or microbiota derived polycyclic aromatic hydrocarbons could directly interfere with the AhR in T cells. Similarly, other small molecules of either source could also exert an influence. Dietary salt would be sensed through SGK1 in T cells and thus favor a Th17 response. Furthermore, the local innate immune system (e.g. intraepithelial lymphocytes) can modulate T cells after interacting with the luminal bacteria. Influence on APCs by most of these mechanisms is also possible (not depicted). Subsequently, T cells could either infiltrate the CNS directly or enter the circulation with a pre-commitment to the Th17 phenotype to be unleashed in a later priming event. (b) Dendritic cells can engulf bacterial components from the intestinal lumen and then migrate into the draining lymph nodes. Although it is a well-established concept that these gut-derived DCs instruct T cells to home back to the dendritic cells' origin, it is conceivable that under certain conditions the T cells may be diverted to enter the CNS. (c) Nutrition or microbiota derived molecules could be carried into extra-intestinal lymphatic organs by convection in lymph or blood vessels, eventually influencing T cells in SLOs. Before this, an effect on lymphocytes within the liver after passing through the portal vein is also possible (not depicted).


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Plasticity of Th17 cells

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Th1 and Th2 cells were described as inherently stable T cell subsets (Murphy et al., 1996). Together with the finding that Th1 and Th2 differentiation programs were mutually exclusive and were governed by some “master” transcription factors, this prompted the idea that T helper cell subsets could be conceptualized as “lineages”. Although the signature cytokines of Th1 and Th2 cells cross-inhibit the development of Th17 cells, and the transcriptional program of Th17 cells is absolutely dependent on the transcription factor ROR-γt, investigators were reluctant to call Th17 cells a “lineage” because these cells appeared to come

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Th17 effector functions

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Inflammation, demyelination and axonal damage constitute the pathological hallmarks of CNS autoimmunity. Breakdown of the blood brain barrier (BBB) with subsequent infiltration of mononuclear cells is considered an essential prerequisite for the development of autoimmune inflammatory lesions in the CNS (Kermode et al., 1990). The mechanisms of this barrier dysfunction are incompletely understood but assumed to involve a detrimental combination of distinct cytokines, chemokines and metalloproteinases produced by infiltrating as well as resident cells (Minagar and Alexander, 2003). The mode of action for Th17 cell involvement in this destructive cascade has only partially been unraveled so far. Here, we will review the role archetypal members of the Th17 cytokine profile play in CNS autoimmunity, covering the signature cytokine IL-17, the recently highlighted granulocyte macrophage colony factor (GM-CSF), and other molecules like IL-9, IL-21, and IL-22 (Korn et al., 2009; Ouyang et al., 2008). Before discussing their individual contribution, we will briefly address the composition, cellular sources and receptor distribution for these cytokines. The IL-17 family consists of six members in total, designated IL-17AF. Both, IL-17 (IL-17A) and IL-17F are produced by Th17 cells and can either form homodimers or IL-17A/IL-17F heterodimers (Korn et al., 2009). Of these, IL-17 homodimers exhibit the highest inflammatory potency (Liang et al., 2007). Apart from certain CD4+ T cells, other immune cell types such as CD8+ T cells, γδ T cells, NK cells, lymphoid tissue inducer-like cells and neutrophils produce IL-17 (Korn et al., 2009). IL-17 binds to IL-17R (IL-17RA) and IL-17RC which are both expressed on a variety of cells including astrocytes and microglia (Das Sarma et al., 2009; Kawanokuchi et al., 2008). IL-17R has a much higher affinity for IL-17 than for IL-17F (Ely et al., 2009; Liu et al., 2013).

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While the entry of generic lymphocytes into the CNS is a well characterized process (Engelhardt and Ransohoff, 2012), the distinct molecular cues for Th17 cell trafficking to the CNS have not been addressed extensively. One report suggested that Th17 cells – by expressing CCR6 – used the epithelium of the choroid plexus (which expresses the CCR6 ligand CCL20) to access the subarachnoid space and operate as “pioneering” cells to initiate inflammation (Reboldi et al., 2009). We and others recently showed that Th1 and Th17 cells, albeit both capable of inducing EAE in mice, entailed diseases with different pathological and clinical features in dependence of their integrin equipment (Glatigny et al., 2011; Rothhammer et al., 2011). Specifically, transferred MOG-specific Th17 cells brought about an atypical EAE with predominating ataxia rather than paralysis, reminiscent of supraspinal lesions that were indeed preferentially triggered by the transferred Th17 cells (Jäger et al., 2009; Kroenke et al., 2008; Lees et al., 2008; Stromnes et al., 2008). This pattern of CNS infiltration by Th17 cells was mediated by the integrin LFA-1, whereas Th1 cells targeted the spinal cord in a VLA-4 dependent manner (Glatigny et al., 2011; Rothhammer et al., 2011). Therefore, in the absence of VLA-4, Th17 cells could still enter the CNS. Interestingly, natalizumab that blocks VLA-4 failed to be efficient in neuromyelitis optica patients who are believed to exhibit a Th17 cell driven disease pathology (Kleiter et al., 2012; Varrin-Doyer et al., 2012).

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in different flavors (see above) and seemed to be exquisitely “plastic” (see also Fig. 2). Fate tracking reporter systems have been developed to monitor Th17 cells in vivo. During EAE, about one fourth of all CD4+ T cells in the spinal cord that had previously produced IL-17, now produced IFN-γ instead. Conversely, the vast majority of all IFN-γ producers, i.e. about 70%, had previously produced IL-17 while only 30% were bona fide Th1 cells with no preceding IL-17 production (Hirota et al., 2011). Thus, Th17 cells “convert” into IFN-γ producers. The molecular underpinnings of this process have been in part investigated. It appears that IL-23 is important for the “re-programming” of Th17 cells into T cells that produce IFN-γ in vivo, designated as Th17/1 cells. In these cells, T-bet was shown to down-modulate the expression of ROR-γt by inhibiting its Runx-1 mediated transactivation. This might result in the loss of IL-17 production in previous Th17 cells (Lazarevic et al., 2011). A more recent report suggested that IL-23 might drive the expression of IFN-γ in Th17 cells independently of T-bet (Duhen et al., 2013). In humans, Th17/1 cells have also been isolated from inflamed tissue of IBD patients as well as from MS lesions (Kebir et al., 2009). A series of surface markers have been suggested for these cells including a combination of CCR6 and CD161 (Annunziato et al., 2007; Cosmi et al., 2008) as well as a combination of CCR6 and CXCR3 (Acosta-Rodriguez et al., 2007). As compared with bona fide Th1 cells, specific molecules like the transcription factor AhR are private to ex-Th17 cells (and are not expressed in bona fide Th1 cells). IL-23R, IL-1R and CCR6 that are also comprised in the Th17 transcriptional program, persist in reprogrammed Th17 cells. Thus, although both subsets produce IFN-γ, Th1 cells and ex-Th17 cells might fundamentally differ in their homing behavior, their response to the innate cytokine milieu in inflamed tissues as well as their mode of cell death and way of regulation by regulatory T cells (Tregs, see below). In addition, Th17 cells also respond to IL-12 (Lee et al., 2009), which might lead to yet another re-programming outcome in vivo.

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of elevated sodium chloride concentration enhanced the generation of Th17 cells in vitro and increased their expression of ROR-γt, IL17 and IL-23R in both murine (Wu et al., 2013) and human T cells (Kleinewietfeld et al., 2013). Intriguingly, both groups report that mice fed with a high-salt diet and subjected to actively induced EAE, showed an exacerbated disease course with increased frequencies of Th17 cells in the CNS. This effect was found to be in part dependent on the salt-sensing kinase SGK1 (serum/glucocorticoid regulated kinase 1), in that mice lacking this enzyme specifically in T cells exhibited a less dramatic EAE increase under high-salt diet (Wu et al., 2013). These reports are of particular interest in light of an increasing salt intake in western countries (Brown et al., 2009) and the partially overlapping rise in MS incidence (Koch-Henriksen and Sørensen, 2010). However, a high-salt diet does not increase salt concentration in most extraintestinal immune compartments and thus a definite mode of action for the effect in mice is still to be revealed. Therefore, despite the tempting correlation, extensive studies in men are necessary before implying a genuine causality between dietary salt and autoimmune diseases like MS. For all described mucosal effects on EAE, it will remain a crucial challenge for future research to investigate whether the described CNS pathology is conveyed by the exact same cells found to be induced or modulated in mucosal tissues or is instead facilitated by auxiliary cells or systemic effects, impacting on distant effector cells resident in lymphoid tissues (Fig. 1). In any case, the recent discoveries in this area of mucosal immunity have spurred microbial and nutritional studies in men that will potentially help to advance our understanding of the human disease.

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direct disruption of the BBB by IL-17 and IL-22, mediated by modulation of endothelial tight junctions (Kebir et al., 2007). In an in vitro model of the BBB, these features enabled Th17 cells to cross a microvascular endothelial monolayer more efficiently than Th1 cells or uncommitted T lymphocytes. Furthermore, IL-17 signaling provoked excess oxidative stress in these endothelial cells which in turn activated their contractile machinery, leading to a downregulation of the tight junction molecule occludin and eventually to an impaired barrier function (Huppert et al., 2010). There is also evidence for a direct effect of IL-17 on CNS-resident cells. When an important component of the IL-17R signal transduction pathway (Gaffen, 2009), the NF-κB activator 1 (Act1), was specifically deleted in cells of neuroectodermal origin (i.e. neurons, astrocytes, and oligodendrocytes), this resulted in reduced EAE severity (Kang et al., 2010). In contrast, ablation in endothelial cells, macrophages or microglia had no effect. In the follow-up study, this effect could be narrowed down to NG2+ glial cells which represent oligodendrocyte progenitors (Kang et al., 2013). Furthermore, IL-17 inhibited the maturation and reduced the survival of oligodendrocyte lineage cells in vitro. In another study, IL-17 alone did not affect survival of oligodendrocytes, but provoked exacerbation of TNF-α induced oligodendrocyte loss and inhibited differentiation of oligodendrocyte progenitor cells (Paintlia et al., 2011). Finally, there is also evidence that direct interactions of Th17 cells with neurons in demyelinating lesions induce severe neuronal dysfunction (Siffrin et al., 2010), whereas the exact mechanism remains enigmatic. In summary, there is evidence for a wide range of proinflammatory and neurotoxic effects exerted by IL-17 in CNS autoimmunity. However, several studies have shown that IL-17 signaling is dispensable for the induction of EAE in that deficiency or neutralization of IL-17 at best entailed attenuation but never complete resistance to the disease (Chen et al., 2006; Haak et al., 2008; Komiyama et al., 2006; Kroenke et al., 2008; Tigno-Aranjuez et al., 2009; Uyttenhove and Van Snick, 2006). Several factors could account for this phenomenon: First, in the absence of IL-17 producing Th17 cells, other T cell subsets such as Th1 cells might compensate via IL-17 independent effector mechanisms. Second, other Th17 derived proinflammatory cytokines such as GMCSF, IL-9, IL-21 or IL-22 could drive the pathology in the absence of IL-17. Indeed, it was known even before the rise of the Th17 concept that genetic deletion of GM-CSF in all murine cells resulted in complete resistance to EAE (McQualter et al., 2001). More recent studies refined this observation and attributed the lack of EAE pathology specifically to the absence of GM-CSF producing CD4+ T lymphocytes, most notably

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GM-CSF is part of the CSF family of hematopoietic growth factors. Although this cytokine is produced by a multitude of different cells, T cells represent the major source of GM-CSF under inflammatory conditions. It signals through a heterodimeric receptor consisting of a unique α-chain and a common β-chain. GM-CSF acts on various cell types controlling activation and survival of macrophages, neutrophils and eosinophils. It is also involved in the maturation of DCs as well as the differentiation of NKT cells and alveolar macrophages (Hamilton, 2008). IL-9 is mainly produced by T cells and has initially been described as an autocrine growth factor which is also active in mast cells. The IL-9R is composed of two subunits: the private α-chain (IL-9Rα) and the common γ-chain (γc) shared by other cytokines including IL-2 and IL-21. The receptor is expressed on various hematopoietic cells such as T cells, B cells and mast cells, while non-hematopoietic targets probably include epithelial and smooth muscle cells (Goswami and Kaplan, 2011). IL-21 belongs to the IL-2 family of cytokines and is expressed in various CD4+ T cell subsets as well as NKT cells. Apart from its abundant expression in Th17 cells, IL-21 is also produced by Th2 cells and follicular T helper cells (Tfh), a specialized population of follicular CD4+ T cells involved in B cell help. IL-21R is composed of the γc and a private IL-21 receptor chain (IL21R). The IL21R is expressed on a plethora of hematopoietic cell types, including T cells, B cells, NK cells, DCs, and macrophages, indicative of the highly pleiotropic effects exerted by IL-21. Indeed, it does not only modulate various aspects of T cell biology but is simultaneously involved in the expansion of B cells and their class switch recombination of immunoglobulin isotypes (Ouyang et al., 2008). IL-22 is a member of the IL-10 family of cytokines and IL-22R and IL10R2 were identified as the heterodimeric receptor complex mediating IL-22 signaling. T cells are its main cellular source. Whereas IL-10R is ubiquitously expressed, IL-22R expression is restricted to tissueresident cells (Ouyang et al., 2008). How do these individual cytokines contribute to the proinflammatory features of Th17 cells observed in CNS autoimmunity? In a cascade of downstream effects, IL-17 induces a distinct set of cytokines and chemokines that eventually promote neuroinflammation: For instance, IL-17 can stimulate epithelial cells to produce CXCL1 and CXCL2 (Kolls and Lindén, 2004), two chemokines that have been detected within EAE and MS lesions (Das Sarma et al., 2009; Filipovic et al., 2003). These so-called ELR+ chemokines attract neutrophils that drive inflammation and activation of the BBB (Carlson et al., 2008). Consequently, large numbers of leukocytes can be recruited to the perivascular white matter. In addition to these indirect effects, there is also evidence for

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Fig. 2. Plasticity of Th17 cells. Th17 cells are increasingly perceived to exhibit a particular tissue- and context-dependent plasticity. The endpoints of this dynamic system appear to be a phenotype rather involved in tissue remodeling (left) and a highly destructive phenotype involved in efficient pathogen clearance but also autoimmunity (right). The hallmark transcription factor of both extremes is ROR-γt while additional environmental and transcriptional cues further define the outcome of the Th17 response. Under the influence of IL-23, Th17 precursor cells or previously IL-17 producing T helper cells would acquire a destructive phenotype including the secretion of IFN-γ, GM-CSF, and other cytokines. While this might be in part mediated by T-bet signaling, it is not absolutely required for this phenotype. On the opposite, as yet only partially characterized signals (e.g. TGF-β1 and IL6 in the absence of IL-23 in vitro but not necessarily in vivo) drive a Th17 response that, by trend, carries out regulatory and remodeling functions via IL-10 and IL-17, respectively. In part, this could be directed by signaling via AhR although the effect is dependent on the specific AhR-ligand. Another potential transcription factor involved in this phenotype is the proto-oncogene c-Maf.


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Interestingly, IL-17 mRNA and protein levels have been found to be elevated in circulating leukocytes and cerebrospinal mononuclear cells of MS patients, in particular during relapses (Brucklacher-Waldert et al., 2009; Durelli et al., 2009; Matusevicius et al., 1999; VakninDembinsky et al., 2006). In line with these findings, microarray approaches revealed increased transcripts encoding IL-17 and RORC (gene name for ROR-γt) in MS plaques compared to normal brain tissue (Lock et al., 2002; Montes et al., 2009). Furthermore, immunohistochemical studies detected IL-17 positive CD4+ and CD8+ T cells in active MS lesions (Tzartos et al., 2008). Interestingly, increased IL-17 production of mononuclear cells in response to myelin basic protein correlated with disease activity as determined by magnetic resonance imaging (Hedegaard et al., 2008). Several studies have addressed the question whether therapeutic agents utilized in the therapy of MS patients have the potential to influence the differentiation or activity of Th17 cells. It has been shown that IFN-β, one of the first-line disease modifying agents in MS, inhibited Th17 differentiation in vitro (Durelli et al., 2009; Ramgolam et al., 2009). These effects of IFN-β are possibly mediated by direct and indirect mechanisms. IFN-β shifted cytokine production of APCs such as DCs from rather pro-inflammatory cytokines such as IL-1β or IL-23 to anti-inflammatory cytokines such as IL-27 (Ramgolam et al., 2009; Sweeney et al., 2011) arguing in favor of an indirect effect of IFN-β on Th17 cell development. In contrast, IFN-β also seemed to directly inhibit differentiation of naïve T cells into Th17 cells (Ramgolam et al., 2009). Interestingly, poor response to IFN-β coincided with higher IL-17F serum levels compared to IFN-β responders (Axtell et al., 2010). It was suggested that Th17 mediated disease was paralleled by an endogenous upregulation of IFN-β expression and it was postulated that exogenous administration of IFN-β would therefore not be beneficial any more in these patients. It was even speculated that excess IFN-β could exert detrimental effects under these conditions (Axtell et al., 2011). However, another study revealed no significant difference in IL-17F serum levels between responders and non-responders to IFN-β (Bushnell et al., 2012), thus refuting the idea to use serum IL-17F levels as a biomarker to stratify patients for the allotment of IFN-β therapy. Other agents used in the treatment of MS patients such as fingolimod (FTY-720) or dimethyl fumarate have also been implicated with a reduction of the Th17 response (Mehling et al., 2010; Peng et al., 2012). So far, it is not clear whether a more specific blockade of the Th17 pathway has beneficial effects in MS patients. Treatment with an antibody directed against IL-12p40 and therefore neutralizing both IL-12 and IL-23 did not result in a significant reduction of disease activity (Segal et al., 2008). However, this study had several drawbacks. First, it is not clear whether the antibody reached the CNS in sufficient quantities. Second, it is not known what effect neutralization of both IL-12 and IL-23 has on already established Th1 or Th17 cells. In this context,

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As described above, Th17 cells can facilitate a strong inflammatory response. These effects not only are required in host defense but also need to be properly controlled in order to avoid excessive immunopathology. Also, under physiological conditions, erroneous activation of Th17 precursor cells has to be prevented. Foxp3+ Tregs contribute critically to the preservation of immune homeostasis. However, it is not clear whether they utilize universal mechanisms to mediate their suppressive activity or whether their approach is individually tailored for different types of effector responses. Several functional studies of transcription factors have demonstrated that Treg responses mirror the effector T cell response on a molecular level. Rudensky and colleagues showed that Treg-specific ablation of Stat3, a key transcription factor for Th17 cell differentiation, resulted in an uncontrolled Th17 cell response (Chaudhry et al., 2009). This was putatively mediated via the production of IL-6 and TGF-β by Stat-3 deficient Treg cells. Furthermore, Stat-3 deficiency in Tregs resulted in lower levels of CCR6, a chemokine receptor involved in migration to sites of Th17 inflammation. In a subsequent study, the same group reported that Tregs needed to sense IL-10 in order to control Th17 mediated inflammation. Their data suggested a positive feedback loop in which signaling via the IL-10R on Tregs led to the Stat3-dependent

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expression of further IL-10, collectively containing Th17 responses (Chaudhry et al., 2011). IL-10 is known to serve as a potent negative regulator of inflammation (Jankovic et al., 2010) and several studies have suggested that IL-10 inhibits differentiation of Th17 cells in a direct and indirect manner (Gu et al., 2008; Li and Flavell, 2008; McGeachy et al., 2007). Some of these data indicated that the IL-10 loop of effector T cell control was particularly important for Th17 responses and less relevant for Th1 or Th2 responses. Another option to preserve immune homeostasis is the elimination of activated T cells by cell intrinsic mechanisms, for example by activation-induced cell death (AICD). In this process, TCR signaling leads to apoptosis, mainly mediated by Fas. Several studies have shown that Th17 cells undergo Fas-mediated AICD, even though they were less susceptible than Th1 cells (Fang et al., 2010; Zhang et al., 2008).

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Th17 cells (Codarri et al., 2011; El-behi et al., 2011). In particular, adoptively transferred, autoaggressive T cells that were unable to produce GM-CSF failed to induce disease and abrogation of GM-CSF by monoclonal antibody treatment reduced EAE severity. Of note, Th17 cells produced GM-CSF in an IL-23 dependent manner (Codarri et al., 2011; El-behi et al., 2011) and GM-CSF in turn triggered IL-23 production by APCs, thus establishing a positive feedback loop (El-behi et al., 2011; Sonderegger et al., 2008a). Mechanistically, the pathogenic targets of GM-CSF were likely cells of myeloid origin that were recruited to the CNS (Codarri et al., 2011) and activated (El-behi et al., 2011) under the influence of this cytokine. However, details on the exact mode of action remain to be elucidated and human trials will have to show whether antibody treatment against GM-CSF is beneficial in autoimmune diseases. In contrast to GM-CSF, the role of IL-9 in CNS autoimmunity is still largely controversial. One study reported that neutralization of IL-9 or deficiency in IL-9 receptor expression resulted in delayed onset of EAE (Nowak et al., 2009) whereas another study observed an earlier onset of disease combined with an even more severe disease course in IL-9 receptor deficient mice (Elyaman et al., 2009). Studies on the role of IL-21 and IL-22 have clearly shown that these two cytokines were dispensable for the induction of EAE (Coquet et al., 2008; Kreymborg et al., 2007; Sonderegger et al., 2008b). A final effector mechanism to be discussed here is the intriguing interaction of Th17 cells with B cells. Meticulous histological analysis of mice subjected to adoptive transfer of encephalitogenic Th17 cells revealed that the development of EAE in this model was accompanied by the formation of ectopic lymphoid follicles in the CNS (Jäger et al., 2009). These structures contained clusters of B cells, in part well organized by reticulin fibers, indicative of a specific accumulation. The presence of ectopic follicles was partially mediated by IL-17 and the cell surface molecule Podoplanin that was expressed on Th17 cells but not on other Th subsets (Peters et al., 2011). These observations are in line with reports, that Th17 cell derived IL-17 promoted the generation of germinal centers (Hsu et al., 2008; Mitsdoerffer et al., 2010). As IL-21 is known to be of particular importance in B cell biology it was tempting to speculate that IL-21 is also involved in the process of ectopic follicle formation. However, disease development and follicle formation was independent of IL-21 signaling in host cells (Peters et al., 2011). The discovered processes are of notable interest since ectopic lymphoid follicles can also be found in the CNS of MS patients with a chronic progressive disease course (Magliozzi et al., 2007; Serafini et al., 2004).

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This work was supported by a Ph.D. fellowship to C.S. from Boehringer Ingelheim Fonds, grants by the German Research Foundation (DFG) to T.K. (Heisenberg, TR128, SFB1054) and M.M. (SyNergy) as well as intramural grants to M.M. from the Technische Universität München (KKF).

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Inflammatory demyelination in multiple sclerosis is most likely the result of an antigen specific adaptive immune response. The priming of lymphocytes and the commitment of T cells to a specific cytokine phenotype happens in the peripheral immune system. Th17 cells appear to play a paramount role in autoimmune tissue inflammation due to their exclusive repertoire of effector functions that are mediated by secretion of IL-17, GM-CSF and other molecules. Whether mucosa associated lymphoid tissue has a prominent role in the differentiation of Th17 precursor cells is an intriguing hypothesis that needs to be further validated. Because of the important role of IL-17 in barrier function at epithelial surfaces, the cellular sources of IL-17 that include Th17 lymphocytes but also cells of the innate immune system (like ILC3 cells) are equipped with a molecular machinery to sense and integrate environmental cues and translate them into appropriate immune responses. The latest insights into these mechanisms might help to provide us with a cell biological framework that translates environmental triggers into disease susceptibility. Besides the ongoing hunt for relevant autoantigens in MS, this new concept could be a rich source for further discoveries that might eventually be exploited for therapeutic approaches. Until then, a greater understanding of Th17 cell biology as well as the exploration of specific biomarkers that are dependent on or coincide with Th17 responses could provide invaluable tools to stratify patients for already existing therapies.

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The authors declare no conflict of interest.

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after some promising preliminary data, it will be interesting to see whether the monoclonal antibody secukinumab, directed against IL-17A, will show beneficial effects in MS patients in the ongoing larger phase IIb study and eventually in a phase III trial. From the immunologic analysis of various recent MS therapy trials emerges the concept that distinct treatment regimens – either by design or incidentally – affect various T cell subsets in a differential manner. The consequential question is whether this knowledge can be used to stratify patients for distinct treatments more efficiently. So far, the disease course of MS patients has mainly been used to discern subtypes of MS in relapsing–remitting, secondary progressive, and primary progressive. However, it is known that patients exhibit significant differences with regard to lesion location, histological features, or various “biomarkers” in the CSF. It will be a major challenge to integrate this additional information and perhaps correlate it with a distinct immunologic reaction type on an individual basis. For example, in Asian patients, two different subtypes of MS can be distinguished: optico-spinal MS (OS-MS) and conventional MS. Whereas lesions in OS-MS patients are primarily localized in the optic nerve and spinal cord, patients with conventional MS exhibit lesions scattered throughout the CNS including the brain. Interestingly, OS-MS patients showed significantly higher levels of IL-17 and IL-8, the functional homolog of mouse CXCL1, in the CSF than conventional MS patients. It was particularly intriguing that IL-8 levels were positively correlated with clinical parameters, measured by the expanded disability status scale (EDSS), as well as the length of spinal cord lesions detected by MRI. Histological analysis revealed massive infiltration of neutrophils in necrotic spinal cord lesions in autopsies of 3 out of 6 OS-MS patients (Ishizu et al., 2005). Notably, patients suffering from neuromyelitis optica, another demyelinating disease of the CNS predominantly affecting the optic nerves and spinal cord, showed increased frequencies of Th17 cells (Varrin-Doyer et al., 2012; Wang et al., 2011). In summary, there was evidence for a “Th17 mediated disease” in OS-MS patients whereas patients affected by conventional MS exhibited a more Th1 like reactivity in their immunologic evaluation. Even though European MS patients do not show such a clear distinction, it is possible that there are patients with a disease type that is, by trend, predominantly mediated by Th1 effects and others that exhibit more prominent Th17 features.

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Microbial view of central nervous system autoimmunity.

CEACAM1 mediates B cell aggregation in central nervous system autoimmunity.

Role and therapeutic value of dendritic cells in central nervous system autoimmunity.

Gut environment-induced intraepithelial autoreactive CD4(+) T cells suppress central nervous system autoimmunity via LAG-3.

Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells.

Th17 cells in inflammation and autoimmunity.

Th17 cells in immunity and autoimmunity.

Gut microbiome and the risk factors in central nervous system autoimmunity.

Development of central nervous system autoimmunity is impaired in the absence of Wiskott-Aldrich syndrome protein.

The Diverse Roles of Microglia in the Neurodegenerative Aspects of Central Nervous System (CNS) Autoimmunity.

Myelin oligodendrocyte glycoprotein has a dual role in T cell autoimmunity against central nervous system myelin.

Central nervous system regeneration.

Central nervous system toxicity.

Central nervous system salicylate.

Central nervous system tuberculosis.

Oxysterols regulate encephalitogenic CD4(+) T cell trafficking during central nervous system autoimmunity.

Primary Central Nervous System Lymphoma.

Drosophila Central Nervous System Glia.

Central nervous system polyarteritis nodosa.

Isolation of Central Nervous System (CNS) Infiltrating Cells.

Purification and culture of central nervous system endothelial cells.

Primary central nervous system lymphoma.

Central nervous system multiple myeloma.

Autoimmunity beyond Th17: GM-CSF producing T cells.