A cellular and molecular view of T helper 17 cell plasticity in autoimmunity

Journal of Autoimmunity xxx (2017) 1e15

Contents lists available at ScienceDirect

Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm

Review article

A cellular and molecular view of T helper 17 cell plasticity in autoimmunity Ralph Stadhouders a, b, Erik Lubberts c, Rudi W. Hendriks a, * a

Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, The Netherlands Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands c Department of Rheumatology, Erasmus MC Rotterdam, Rotterdam, The Netherlands b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 6 December 2017 Accepted 6 December 2017 Available online xxx

Since the original identification of the T helper 17 (Th17) subset in 2005, it has become evident that these cells do not only contribute to host defence against pathogens, such as bacteria and fungi, but that they are also critically involved in the pathogenesis of many autoimmune diseases. In contrast to the classic Th1 and Th2 cells, which represent rather stably polarized subsets, Th17 cells display remarkable heterogeneity and plasticity. This has been attributed to the characteristics of the key transcription factor that guides Th17 differentiation, retinoic acid receptor-related orphan nuclear receptor gamma (RORg). Unlike the ‘master regulators’ T-bet and GATA3 that orchestrate Th1 and Th2 differentiation, respectively, RORg controls transcription at relatively few loci in Th17 cells. Moreover, its expression is not stabilized by positive feedback loops but rather influenced by environmental cues, allowing for substantial functional plasticity. Importantly, a subset of IL-17/IFNg double-producing Th17 cells was identified in both human and mouse models. Evidence is accumulating that these IL-17/IFNg double-producing cells are pathogenic drivers in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. In addition, IL-17/IFNg double-producing cells have been identified in disorders in which the role of autoimmunity remains unclear, such as sarcoidosis. The observed plasticity of Th17 cells towards the Th1 phenotype can be explained by extensive epigenetic priming of the IFNG locus in Th17 cells. In fact, Th17 cells display an IFNG chromatin landscape that is remarkably similar to that of Th1 cells. On the other hand, pathogenic capabilities of Th17 cells can be restrained by stimulating IL-10 production and transdifferentiation into IL-10 producing T regulatory type 1 (Tr1) cells. In this review, we discuss recent advances in our knowledge on the cellular and molecular mechanisms involved in Th17 differentiation, heterogeneity and plasticity. We focus on transcriptional regulation of the Th17 expression program, the epigenetic dynamics involved, and how genetic variants associated with autoimmunity may affect immune responses through distal gene regulatory elements. Finally, the implications of Th17 cell plasticity for the pathogenesis and treatment of human autoimmune diseases will be discussed. © 2017 Published by Elsevier Ltd.

Keywords: Autoimmune disease Cytokine Epigenetics Plasticity T helper cell Th17 Transcription factor Transdifferentiation

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . T helper subset differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Th1 cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Th2 cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Th17 cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. TGFb in Th17 and Th9 cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Th22 cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author. Department of Pulmonary Medicine, Erasmus MC Rotterdam, PO box 2040, 3000 CA Rotterdam, The Netherlands. E-mail address: [email protected] (R.W. Hendriks). https://doi.org/10.1016/j.jaut.2017.12.007 0896-8411/© 2017 Published by Elsevier Ltd.

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2.6. IL-21 in Th17 and Tfh cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Regulatory T cell populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8. Evidence for a continuum of Th cell fates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular biology of Th subset differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. TFs and the chromatin landscape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Epigenome dynamics in Th17 cell differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Transcriptional control and the genetics of autoimmune disease susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Th17 cells in inflammation and autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Discovery of Th17 cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Induction and regulation of Th17 differentiation in human and mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Direct evidence for a role of Th17 cells in autoimmunity and host defense . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Th17 subset plasticity and autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Th17 subpopulations and pathogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Th17 plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction CD4þ T helper (Th) cells are central orchestrators of immune responses. They provide help to CD8þ T cells and B cells and produce cytokines that activate or modulate innate immune cells, stromal cells and epithelial cells. Following the recognition of their cognate antigen on the surface of antigen presenting cells (APCs) by the T cell receptor (TCR), activated CD4þ T cells are triggered to differentiate into effector Th cells, guided by specific co-stimulatory signals and the cytokine milieu. In 1986 Mossmann, Coffman and colleagues first reported that upon antigenic stimulation naive CD4þ T cells can differentiate into two functionally distinct subsets: Th1 or Th2 effector cells [1]. This division was based on cytokine production profiles and provided an explanation for the diverse responses of effector CD4þ T cells in infection, allergy or autoimmunity. Th1 cells mainly produce IFNg and TNF-a and are crucial for host defense against intracellular bacteria and viruses, but are also involved in the pathogenesis of autoimmune disorders. Th2 cells produce the signature cytokines IL-4, IL-5 and IL-13 to control helminth infections and are implicated in allergic immune responses. Differentiation into Th1 or Th2 cells is controlled by the key sequence-specific DNA-binding proteins (transcription factors, TFs) T-bet, encoded by the TBX21 gene [2,3] and GATA3 [4,5] respectively, and involves epigenetic mechanisms that drive subset-specific differentiation and restriction of alternative fates. Since IL-12, IFNg and T-bet have the capacity to repress Th2 polarization and, conversely, the IL-4-GATA3 axis represses Th1 differentiation, it appears that Th1 and Th2 cells represented mutually exclusive and stable, self-reinforcing, terminally differentiated subsets. This dichotomous Th1/Th2 division paradigm was challenged by the identification of highly stable TbetþGATA3þ bifunctional Th1/Th1 hybrid cells that co-produced IFNg and IL-4 at the single-cell level [6e8]. Moreover, to date Th cell differentiation has been extended to include various additional polarization states, including regulatory T cells (Tregs), Th9, Th17, Th22, follicular T helper cells (Tfh) and follicular Tregs (Tfr). Each of these subsets is characterized by a unique cytokine expression pattern and a lineage-associated TF network (Fig. 1). The Th17 subset, identified in 2005 [9e12], resides mainly at mucosal sites such as in the gastrointestinal tract and the airways. These T cells secrete various cytokines including IL-17A, IL-17F, IL21, IL-22 and granulocytes macrophage colony-stimulating factor (GM-CSF). Although Th17 cells were originally discovered in the context of autoimmune disease, they play a crucial role in the maintenance of mucosal homeostasis and contribute to the

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protection against bacterial and fungal pathogens, such as Mycobacterium and Candida [13]. The retinoic acid receptor-related orphan nuclear receptor gamma (RORg) is the key TF that orchestrates the differentiation of the Th17 lineage and directly induces transcription of IL-17A/F [14]. However, in contrast to T-bet and GATA3 function in Th1 and Th2 cells, respectively, RORg regulates transcription of remarkably few loci in Th17 cells and its expression is not stabilized by positive feedback loops [15]. Therefore, RORg may not be regarded as a prototypical master regulator that functions to lock-in the Th17 differentiation program. Rather, expression of RORg is influenced by environmental cues, making Th17 cells relatively unstable and allowing for substantial functional plasticity [15]. In particular, a subset of IL-17-producing cells that co-expresses IFNg was identified in both human and mouse models and defined as non-classic Th1 cells, ex-Th17 cells or Th17.1 cells [16,17]. It is thought that following an IL-17/IFNg double-producing phase, Th17 cells may lose IL-17 expression to become an IFNgþ Th1-like cells in which IL-17 expression is almost completely extinguished [17]. On the other hand, studies have shown that TGFb and IL-6, which initially drive Th17 differentiation, can also restrain the pathogenic capabilities of Th17 cells by stimulating IL-10 production [18]. Indeed, fate-mapping studies provided evidence that Th17 cells may lose IL-17A expression and transdifferentiate into IL10-producing Tr1 cells [19]. Given that Th17 cells have a beneficial role in barrier protection as well as a pathogenic pro-inflammatory role in many autoimmune diseases, their heterogeneity and plasticity is not only fundamentally interesting in the context of cell identity and reprogramming, but is also highly relevant for our understanding of autoimmunity and the development of novel therapeutic strategies. Recently, single-cell transcriptome analyses have shed light on the molecular basis of Th17 heterogeneity [20,21]. In this review, we summarize recent advances in our understanding of the molecular mechanisms involved in Th17 cell plasticity. We focus on gene expression programs in the Th17 subset that are regulated by TFs through changes in epigenetic modifications and chromatin structure. Finally, implications for the pathogenesis of human autoimmune diseases will be discussed. 2. T helper subset differentiation Initially Th subset differentiation was thought to rely predominantly on single ‘master’ TFs that enforce lineage commitment and engage in positive auto-regulatory feedback loops and reciprocal

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Fig. 1. Global overview of T helper cell differentiation. Schematic depicting the development of the various T helper (Th) subsets, including regulatory T cells (Tregs), from immature (imm.) CD4þ T cells in the thymus. Naive peripheral Th (Th0) cells differentiate into Th1, Th2, Th17, Th9, Th22 and follicular Th (Tfh) cells as a consequence of infection with indicated pathogens or exposure to allergens. Peripheral Tregs (pTreg) and T regulatory type 1 (Tr1) cells also differentiate from Th0 cells. Reported Th17 plasticity routes are indicated with red arrows. Instructive signals for Th/Treg cell differentiation are shown in dark blue; signature secreted signals of differentiated subsets are indicated in dark grey. Key surface molecules of each T cell subset are depicted in black, with master TFs that determine cell fate shown in green and key co-factors indicated in light blue.

cross-regulation. However, a new view has emerged in which Th subset differentiation is orchestrated by complex regulatory networks that allow for shared transcriptional programs and plasticity across T cell subsets. In this section, we will discuss the currently characterized CD4þ T cell subsets, including the signals and nuclear factors that instruct their differentiation. 2.1. Th1 cells Differentiation of Th1 cells is initiated upon TCR stimulation in the presence of either IL-12 or IFNg, which induce signal transducer and activator of transcription 4 (STAT4) or STAT1, respectively. This results in the upregulation of the key Th1 TF T-bet, which direct targets include the Th1 signature genes IFNG and CXCR3 (Fig. 1). In a positive feedback loop T-bet drives Th1 differentiation and antagonizes Th2 and Th17 differentiation by inhibiting GATA3 and RORg function, respectively [22]. IL-2 - a cytokine that is central to T cell activation, proliferation and survival - is also important for Th1 differentiation because it enhances T-bet expression as well as IL-12 responsiveness through the induction of IL-12Rb2 [23]. T-bet can

associate with the transcriptional repressor BCL6 to negatively regulate alternative Th programs [24]. T-bet also cooperates with runt-related TF 3 (RUNX3) to activate the IFNG gene and to silence IL4 [25], and with RUNX1 to block RUNX1-RORg association and inhibit Th17 differentiation as a consequence. In addition, retinoic acid is essential for Th1 lineage stability as it sustains expression of Th1 lineage specifying genes and represses genes that instruct Th17 cell fate [26]. 2.2. Th2 cells Differentiation of Th2 cells is driven by IL-4, which induces STAT6 phosphorylation and activation to enhance transcription of GATA3 (Fig. 1). This TF, which is necessary and sufficient for Th2 cytokine gene expression, can directly upregulate its own expression or via the helix-loop-helix TF DEC2 [27]. The initial IL-4 source that directs the Th2 response remains unclear, although various immune cell types can produce IL-4, including Tfh cells [28,29]. The finding that Tfh cells can differentiate into IL-4/IL-13 double-producing Th2 cells that accumulate in the lung and recruit eosinophils

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in allergic airway inflammation, points at plasticity within the Tfhlineage [29]. IL-2 enhances TCR-induced IL-4Ra expression via STAT5, which binds directly to both the IL4RA locus and the Th2 cytokine locus [30]. In addition, Notch and IL-4R signaling synergize to promote Th2 cell responses via activation of GATA3. Several other TFs have been implicated in the induction, maintenance or repression of Th2 differentiation, many of which directly interact with GATA3 [31]. T cell factor-1 (TCF-1) initiates Th2 differentiation by inducing GATA3 [32]. GFI1 synergizes with GATA3, is important for Th2 cell expansion and is required for GATA3 protein stability [33e35]. Interferon regulatory factor 4 (IRF4) interacts with nuclear factor of activated T cells c2 (NFATc2) and synergizes with NFATc2 and c-MAF to increase IL-4 expression [36]. GATA3 is also expressed at lower levels in Th1 cells, where it has been shown to be distributed away from Th2 genes and interacts with T-bet to bind to T-box motifs [37,38]. Interestingly, GATA3 is also expressed in Tregs residing at barrier sites, in which it forms a complex with the Tregspecific TF Forkhead box protein 3 (FOXP3). In extreme inflammatory settings, GATA3 inhibits the expression of TFs involved in effector T cell differentiation such as RORg, thus limiting aberrant production of IL-17A [39]. 2.3. Th17 cells The TF RORg is essential for the Th17 lineage and is induced by IL-6 and IL-23 via STAT3, which also regulates the IL17A, IL17F and IL23R genes via epigenetic mechanisms [40] as well as IL-21 production (Fig. 1). The latter cytokine can promote pro-inflammatory Th17 cell differentiation, survival and expansion, but is also a signature cytokine produced by Tfh cells [41]. In addition, IL-23, which was originally thought to be the key Th17 inducer, is only required for its expansion and maintenance [42]. IL-12, IFNg and IL4 inhibit Th17 polarization [43]. In addition to STAT3 and RORg many other TFs play an important role in Th17 differentiation, including basic leucine zipper TF ATF-like (BATF), IRF4, fos-related antigen 2 (FOSL2), RORa and aryl hydrocarbon receptor (AHR) [44e48]. STAT3, RORg and RORa activate the expression of canonical Th17 cytokines, including IL-17A, IL-17F, IL-21 and IL-22, as well as IL-23R. The promyelocytic leukemia zinc finger protein (PLZF) is critical for the acquisition and maintenance of the Th17 phenotype and regulates the chemokine receptor CCR6, which is responsible for chemoattraction of Th17 cells to mucosal surfaces under both homeostatic and inflammatory conditions via its ligand CCL20 [49]. Finally, environmental cues are linked to various metabolic states that impact T-cell fate determination: accumulation of 2-hydroxyglutarate in T cells inhibits FOXP3 transcription, which is essential for Th17 differentiation [50,51]. 2.4. TGFb in Th17 and Th9 cells High doses of TGFb induce FOXP3 expression and thereby promote Treg differentiation, but low doses of TGFb - together with IL6 - induce Th17 polarization. However, TGFb does not seem to be essential, as in mice the combination of IL-6, IL-1b and IL-23 is sufficient for the development of Th17 cells [52]. In combination with IL-4, TGFb induces the development of a specific Th subset that preferentially expresses IL-9, named Th9 cells (Fig. 1). This cell population is different from Th2 cells, which originally were thought to be the main source of IL-947, [53]. In the presence of TGFb, IL-4 fails to induce GATA3, because TGFb suppresses GATA3 through the Sox4 TF [54,55]. IL-9 is implicated in allergic airway inflammation and asthma and increases mast cell recruitment, proliferation and cytokine production [56]. Moreover, recent studies have shown that IL-9 contributes to various autoimmune diseases, including systemic lupus erythematosus (SLE), multiple

sclerosis (MS), inflammatory bowel diseases (IBD), rheumatoid arthritis (RA) and psoriasis [57]. When cultured in the presence of TGFb, Th17 cells also produce IL-9 [58]. The finding that IL-9 neutralization or IL-9R deficiency attenuates myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, indicates that IL-9 contributes to Th17-driven inflammatory disease [59]. In contrast, IL-9 enhances the suppressive functions of Tregs in vitro, and it was reported by another group that the absence of IL-9 signaling is associated with exacerbation of MOG peptide-driven EAE [60]. More experiments are required to investigate the mechanisms involved in IL-9 function as a pathogenic pro-inflammatory or as a regulatory and protective cytokine. A key TF that is critical for Th9 differentiation or IL-9 induction in other T cell subsets has not been identified to date, although FOXO1 is required for IL-9 induction in Th9 and Th17 cells and BATF, IRF4 and PU.1 have been implicated in Th9 differentiation [61e63]. 2.5. Th22 cells Besides IL-17, Th17 cells can also produce IL-22. A distinct population of CCR6þIL-17- IL-22-producing cells has been identified, called Th22 cells (Fig. 1) [64e66]. This subset differentiates in response to TNF and IL-6, and production of IL-22 is dependent on the TF AHR. Th22 cells operate at mucosal surfaces: they are an important source of IL-22 for host defense against enteropathogenic Citrobacter rodentium bacteria [67], as well as the pulmonary pathogen Klebsiella pneumoniae [68]. Interestingly, whereas in the airways IL-22 is pro-inflammatory in the presence of IL-17, IL-22 is protective in the absence of IL-17 [69]. IL-22 is a key mediator in the pathogenesis of psoriasis and has been associated with keratinocyte activation and the formation of epidermal acanthosis, a prominent morphologic feature of psoriasis [70]. Moreover, psoriatic patients manifest increased IL-22 plasma levels that correlate with disease severity. 2.6. IL-21 in Th17 and Tfh cells IL-21 is an autocrine cytokine that is critical for Th17 cell differentiation, expansion and survival [41,42,71e73]. On the other hand, IL-21 is a key marker for Tfh cells present in germinal centers (GCs), where they provide help to B cells by supporting proliferation, differentiation and Ig class switch recombination [74,75]. Tfh cells represent another Th subset, which express the chemokine receptor CXCR5 and the immune checkpoint molecule programmed death 1 (PD-1). Their generation is dependent on the transcriptional repressor BCL-6 and involves many other TFs, including c-MAF, TCF-1, IRF4 and STAT3, as well as the cytokines IL6 and IL-21 [74,75]. Deregulation of Tfh cells has been linked to the pathogenesis of autoimmune diseases in which B cells play an important role, such as SLE. 2.7. Regulatory T cell populations Tregs are a very heterogeneous population of CD4þ T cells with suppressive functions that maintain tolerance to harmless food/ self-antigens and prevent autoimmune disease. FOXP3þ Tregs are primarily generated in the thymus, and are often referred to as tTregs (Fig. 1). In addition, TGFb has the capacity to induce Tregs in vivo outside the thymus at peripheral sites (pTregs) or in vitro (iTregs) [76]. IL-10 is important for the suppressive function of Tregs and surface expression of cytotoxic T lymphocyte antigen-4 (CTLA-4) may sequester ligands (e.g. CD80 or CD86 on APCs) away from CD28 to prevent T cell co-stimulation, although it remains unclear how individual Treg populations exert their function

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in vivo. It was originally reported that expression of the Ikaros TF family member Helios discriminates tTregs from pTregs [77]. However, it is now becoming clear that Helios expression can also be induced in pTregs. Heliosþ Treg populations exhibits a more activated phenotype [78,79] and Helios is required for their stable inhibitory activity [80]. Interestingly, it has been reported that Tregs lacking GATA3 [81] or lacking both GATA3 and T-bet [82] were functionally defective, acquired a Th17 cell phenotype, upregulated RORg and downregulated FOXP3. Similarly, CCR6 signaling in induced Tregs inhibits their suppressor function during gut inflammation, enhances RORg expression and redirects them towards the Th17 lineage [83]. By contrast, expression of RORg in FOXP3þ Tregs contributes to their optimal suppressive capacity, as shown in a colitis model and in myelin-specific Th17-mediated central nervous system autoinflammation in mice [84,85]. Thus, the precise function of co-expression of master TFs traditionally associated with other T cell subsets in the various Treg populations remains an unresolved issue. Yet another specific thymus-derived FOXP3þ T cell subset was found to reside in GCs, where it can restrain GC responses. These cells resemble Tfh cells in that they also show high expression levels of BCL6, CXCR5 and PD-1, but function like Tregs and are called follicular regulatory T cells (Tfr) [86e88]. Finally, FOXP3- cells secreting high levels of IL-10 have been described, named T regulatory type 1 (Tr1) cells which can inhibit T cell activity by various mechanisms, including granzyme B and perforin release and inhibitory cell-cell interactions via CTLA-4 or PD-1 [89]. Tr1 cell differentiation and function are induced by IL-27, and rely primarily on the expression of c-MAF, AHR, BLIMP1, IRF1 and BATF. However, no uniquely expressed master TF has been identified in TR1 cells so far. 2.8. Evidence for a continuum of Th cell fates Recently, the application of novel technology has revealed additional layers of complexity involved in Th differentiation, challenging the concept of stable Th subsets even further. Exposure of CD4þ T cells in vitro to numerous combinations of cytokines resulted in a continuum of cell fates, rather than a limited number of distinct phenotypes [90]. The authors used mathematical modeling to explain their findings and to predict cell population responses to input conditions. Mass cytometry (or Cytometry by Time-of-Flight, CyTOF) was used to analyze chemokine receptors and cytokines across eight different human tissues [91]. This highdimensional analysis indicated that human Th cells could not easily be separated into distinct lineages. Several Th subsets with overlapping cytokine expression profiles were identified, suggesting that Th lineages defined in mouse models cannot always be readily distinguished in humans [91]. Interestingly, high-dimensional flow cytometry analysis of T cells from a human cohort demonstrated subject-to-subject expression variation linked to age and diseaseassociated genetic polymorphisms [92]. Likewise, a very recent single-cell RNA sequencing study in mice demonstrated that aging was associated with increased in cell-to-cell transcriptional variability in Th cells [93]. 3. Molecular biology of Th subset differentiation 3.1. TFs and the chromatin landscape As indicated in Fig. 1, gene expression programs implemented by combinations of TFs define Th cell identity and function. These proteins direct the gene regulatory machinery to thousands of genomic regions collectively referred to as gene regulatory elements (GREs). Bound at these GREs, TFs are able to recruit various

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cofactors and protein complexes to modulate the chromatin landscape and/or the expression of their target genes [94]. TFs operate in a highly combinatorial fashion, although certain hierarchies can often be identified (i.e. existence of a master TF) [95]. Transcriptional control from GREs by TFs occurs in two broadly defined nonmutually exclusive manners: at promoter regions within ~5 kb of a gene's transcriptional start site or at GREs located further away (up to several megabases) from genes in introns or intergenic regions. Such distal control elements can be categorized in enhancers and cooperative clusters of enhancers called locus control regions (LCRs) that stimulate transcription or silencers that inhibit gene expression [96]. Distal GREs and their associated TF complexes bridge the distance to their cognate target genes via threedimensional (3D) folding of the genome into topological domains and chromatin loops [97]. The TF-mediated activity of GREs, in particular enhancer elements, is often restricted to specific cell types or states and is therefore the prime determinant of lineagespecific spatio-temporal gene expression and cell identity [98]. Important in the context of TF action and cellular plasticity is the role of the chromatin landscape. TF binding is heavily influenced by chromatin state, which explains why only a fraction of the putative DNA-binding motifs for a TF are occupied in a chromatin context [99]. Several aspects of chromatin mediate the accessibility of a GRE. TF recruitment to GREs is facilitated if the regions are devoid of nucleosomes, with the notable exception of a special class of TFs called pioneer factors that have the capacity to bind to nucleosomal DNA [100]. Post-translational histone modifications, in particular acetylation of histone H3 and H4, also contribute to creating a chromatin environment that is permissive to TF binding, as higher levels of local histone acetylation weaken histone-DNA interactions and promote DNA accessibility [101]. Methylation of the DNA itself provides yet another layer of regulation: DNA methylation can directly impede TF binding or recruit histone deacetylase enzymes to induce a non-permissive chromatin environment [102]. Conversely, TFs are able to engage chromatin modifying protein complexes to alter the local chromatin and DNA methylation state. Epigenetic regulation of gene expression - and cell identity as a consequence - are therefore the result of a complex interplay between TF complexes and the chromatin landscape. 3.2. Epigenome dynamics in Th17 cell differentiation A classic example of how TFs and epigenetic mechanisms shape Th cell identity and function is the activation of the IFNG and Th2 cytokine (IL4, IL5 and IL13) loci during Th1/Th2 polarization, which has been dissected in great molecular detail for murine Th cell differentiation [103e106]. In naive CD4þ T cells, both loci reside in an inert epigenetic state defined by overall histone hypoacetylation and DNA hypermethylation. Under polarizing conditions, STAT4 and T-bet or STAT6 and GATA3 induce lineage-specific changes in the epigenetic landscape of the IFNG locus in Th1 cells and the Th2 cytokine locus in Th2 cells, respectively. As a result, the chromatin landscape of the IFNG locus only becomes transcriptionally permissive in Th1 cells expressing STAT4 and T-bet, while in Th2 cells the locus maintains its inert naive state. The opposite pattern was observed for the Th2 cytokine locus in Th1 and Th2 cells, in which an LCR controlled by STAT6 and GATA3 drives Th2-specific expression of IL4, IL5 and IL13 [103e106]. Of significant relevance here are the dynamics of the 3D organization of these signature cytokine loci. As mentioned above, distal GREs exert their transcriptional effects by interacting with promoters in 3D nuclear space. Interestingly, the Th2 LCR already showed spatial proximity to the cytokine gene promoters in naive CD4þ T cells prior to gene activation [107], thus adopting a poised conformation that allows for a rapid response to specific changes in cytokine milieu (i.e. Th2

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polarizing conditions). By contrast, long-range chromatin interactions between IFNG and its GREs do not occur in naive cells and are established upon Th1 differentiation and T-bet expression [108]. Similar molecular mechanisms control the regulation of the IL17A gene during human Th cell polarization. In naive human CD4þ T cells, the IL17A locus is not permissive to TF binding as it is largely devoid of acetylated histones and nucleosome-depleted regions (Fig. 2A). Moreover, DNA of the IL17A promoter region is heavily methylated in naive or Th1 cells [109], all in accordance with the inactive status of IL17A in these cells. During Th17 differentiation a dramatic epigenetic transformation takes place, as promoter activation and DNA demethylation occurs [109] and various acetylated and nucleosome-depleted distal GREs are established through active regulation by TFs, resulting in IL17A activation (Fig. 2A). Although in-depth molecular studies of human IL17A regulation are still lacking, studies of murine Th17 differentiation indicate that upon TCR stimulation of naive CD4þ T cells, BATF and IRF4 are first recruited to the IL17A locus. These pioneer TF proteins are thought to modify the chromatin landscape to allow Th17-specific RORg binding and IL17A activation [15]. In murine T cells, Th17-specific chromatin looping mechanisms also appear to play a role in the regulation of IL17A expression [110], but these have not been extensive characterized during human Th17 differentiation. Besides driving differentiation, epigenetic mechanisms also provide a means to ensure the stability of a cellular state. By setting up ‘epigenetic safeguards’, cells can impose strict requirements for the activation or repression of genes that could lead to phenotypic instability (e.g. GATA3 expression in a Th17 cell), which under homeostatic conditions is often undesirable [111]. However, cellular plasticity among Th subsets - in particular Th17 cells - is abundant, which means that epigenetic mechanisms are not always able to prevent plasticity. Although this brings the risk of unwanted plasticity, it also creates opportunities for Th cells to adapt to a diverse set of microenvironments [112]. Profiling chromatin landscapes can provide clues on the plastic potential of cells, as was shown for the IFNG locus in Th cell subsets [113]. As expected, a considerable expansion of chromatin accessibility accompanies the differentiation of naive CD4þ T cells to Th1 cells, the latter expressing high levels of IFNg (Fig. 2B). While in Th2 cells the IFNG locus is not substantially remodeled, Th17 cells display a chromatin landscape that is remarkably similar to that of Th1 cells (Fig. 2B) [114]. Extensive epigenetic priming of the IFNG locus in Th17 cells explains the frequently observed plasticity of these cells towards a Th1 phenotype in humans (see below). Such poised epigenetic states at subset-defining loci were common amongst the various murine Th subsets, although they occurred in a highly subset/locusspecific fashion [115]. 3D genome topology, although not systematically explored yet in the context of cellular plasticity, could also contribute to epigenetic priming [116]. For example, close spatial proximity (or ‘contraction’ [117]) between the IFNG promoter and enhancer in Th17 cells, as seen in Th1 cells [108], would prevent the need for local topological remodeling and lower the ‘epigenetic threshold’ for IFNG activation in Th17 cells when exposed to Th1promoting conditions (Fig. 3). Whether such mechanisms contribute to Th cell plasticity in vivo remains to be seen. 3.3. Transcriptional control and the genetics of autoimmune disease susceptibility Genetic variation among humans can disrupt transcriptional regulation and promote disease susceptibility [118]. Currently, 282 genome-wide association studies (GWAS) for 119 autoimmune phenotypes have been published [119]. These studies have identified hundreds of loci containing genetic variants (i.e. single-

nucleotide polymorphisms; SNPs) associated with autoimmune disorders, including those encoding key regulators of Th1 and Th17 cells (e.g. IL23R, STAT3 and IL12RB2) [120]. However, distinguishing causal nucleotide changes from the many neutral variants in genetic linkage is challenging. Moreover, many GWAS loci encode genes that have not been implicated in T cell biology and the vast majority of associated variants locate to poorly characterized non-coding regions of the genome. Hence, translating individual genetic associations into molecular mechanisms that explain why a specific variant or region influences autoimmunity remains problematic. What has since become clear is that GWAS variants are highly enriched in putative distal enhancer regions bound by TFs [121]. Chromatin profiling experiments are well suited to identify active GREs in relevant human cell types and therefore provide a means to directly link genetic variation to gene regulatory mechanisms [122,123]. Several recent studies have taken such an epigenomics approach to link autoimmunity-associated variants to Th subset-specific GREs and explore the underlying mechanisms [124e126]. Farh and colleagues reported that ~70% of computationally selected candidate causal variants (n ¼ 4950) associated with 21 autoimmune disorders were located in GREs active in immune cells. Highly significant enrichments of polymorphisms associated with Crohn's disease, MS, RA and juvenile idiopathic arthritis (JIA) were observed in Th17 enhancers. In several instances, variants altered TF binding motifs and affected gene expression [124]. How might this combination of genetic and epigenetic studies impact the treatment of autoimmune disease? The strength of this unbiased approach resides in its ability to pinpoint those genetic variants that have a functional impact on transcriptional regulation, thus exposing new genes, GREs and pathways as targets for possible therapeutic intervention. Take for example the IL2RA locus encoding the receptor for IL-2. In human Th17 cells, the IL2RA locus contains a cluster of highly active enhancer elements bound by various TFs, which is in accordance with substantial IL2RA expression in these cells [124] (Fig. 2C). These clusters of enhancers, reminiscent of LCRs, have recently been defined as super-enhancers [127]. Super-enhancers are cell type-specific and control the expression of a relatively small subset of core cell identity genes [128]. Strikingly, these super-enhancers were shown to carry the major burden of disease-associated variation, as exemplified by the human IL2RA Th17 super-enhancer that contains many autoimmunity variants (Fig. 2C). Interestingly, engineering of one of these human IL2RA super-enhancer variants in mice revealed defects in IL-2RA upregulation in vivo upon TCR stimulation of naive CD4þ T cells and skewing of Th cell polarization to a Th17 fate in vitro [129], underscoring the relevance of dissecting GWAS loci through epigenomic approaches. Studies aimed at the pharmacological targeting of epigenetic mechanisms made the exciting observation that super-enhancers are particularly vulnerable to various inhibitors of transcriptional activation [130e132]. Indeed, treating human CD4þ T cells from healthy controls with the JAK inhibitor tofacitinib selectively targeted RA risk genes controlled by super-enhancers [125], while exposure of CD4þ T cells from JIA patients to the BET protein inhibitor JQ1 preferentially inhibited JIA-specific super-enhancer driven gene expression [126]. BET protein inhibition was also shown to selectively block human Th17 differentiation and protect mice from experimentally induced autoimmunity [133]. The use of ‘epigenetic drugs’ [134] thus poses a novel and promising therapeutic avenue to suppress autoimmune disease. Collectively, these insights place the epigenetic control of gene expression at the heart of Th cell identity, function and plasticity both in health and disease.

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Fig. 2. Epigenetic mechanisms contribute to Th17 cell differentiation, plasticity and autoimmune disease susceptibility. (A) The chromatin landscape of the human IL17A locus during Th17 differentiation. Various nucleosome-depleted regions (revealed as peaks in the upper two black tracks generated using DNAseI hypersensitivity sequencing; DHS), indicative of TF binding, appear as naive Th cells (Th0) polarize towards Th17 cells and activate IL17A expression (indicated on the right by a ‘þ’). At the same time, nucleosomedepleted promoter and enhancer regions are hyperacetylated (shown as strong dark grey signals of histone 3 lysine 27 acetylation; H3K27Ac), indicating the activation of these gene regulatory elements (GREs). (B) Epigenetic priming of the IFNG locus in human Th17 cells. Known IFNG GREs (indicated by red shading) become active (i.e. nucleosome-depleted, indicated by black peaks) during Th1 polarization to activate gene expression. While little change to the IFNG chromatin landscape occurs in Th2 cells, Th17 cells display a remarkable Th1-like configuration. This indicates epigenetic priming of the IFNG GREs in Th17, providing an explanation for the frequent plasticity of Th17 cells towards Th1features. (C) The chromatin landscape of the human IL2RA locus in Th17 cells. Blue shading indicates a previously identified [124] super-enhancer element that consists of several IL2RA enhancer elements that show exceptionally high levels of H3K27Ac and nucleosome-depletion. The super-enhancer region co-localizes with numerous singlenucleotide polymorphisms (SNPs) associated with various autoimmune disorders, including variants (within the CaRE4 enhancer) that affect IL2RA expression and skew T cell differentiation towards a Th17 phenotype [129]. Th17 cells harbor ~500e600 super-enhancer elements that control cell identity and plasticity, but also disease-associated gene expression. However, they are also hypersensitive to the effects of various (epigenetic) inhibitors, making them potential therapeutic targets. Epigenomic datasets were obtained from the ENCODE [213] and Roadmap Epigenomics [214] consortia databases.

4. Th17 cells in inflammation and autoimmunity 4.1. Discovery of Th17 cells The identification of Th17 cells helped to resolve some inadequacies of the original Th1/Th2 concept that had dominated T

cell immunology for almost 20 years [9,10,135,136]. For a long time, it was thought that the IL-12/IFNg pathway and Th1 cells were central to the development of autoimmune disease. However, in the late 1990s IL-23, consisting of a unique p19 subunit and the IL12p40 subunit of IL-12, was discovered as a new cytokine of the IL12 family [137]. Loss of IL-23, but not IL-12, made mice highly

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Fig. 3. Model showing the 3D chromatin organization of the IFNG and IL17 loci and its potential implications for Th17 plasticity. A schematic representation of chromatin loops connecting enhancers and gene promoters at the IFNG (top) and IL17 (bottom) loci in Th0, Th1, Th17 and pathogenic Th17.1 cells. In non-expressing Th0 cells, a non-contracted conformation does not facilitate promoter-enhancer communication and gene activation. In differentiated Th cells, signature cytokine loci (IFNG in Th1 and IL17 in Th17) adopt a contracted conformation that positions enhancers close to gene promoters to stimulate transcription. A requirement for topological remodeling to activate signature genes of alternative Th cell subsets could represent another epigenetic ‘barrier’ to prevent plasticity. Conversely, topological ‘priming’ could explain the increased occurrence of specific routes of plasticity, analogous to a primed chromatin state (see Fig. 2B). For example, a (partially) contracted conformation of the IFNG locus in Th17 cells could facilitate IFNG activation once Th1-promoting signals appear, while a non-contracted conformation of the IL17 locus in Th1 cells impedes IL17 A/F activation under Th17 polarizing conditions.

resistant to autoimmune diseases such as EAE and collageninduced arthritis (CIA), a model for RA [138,139]. These findings indicated that IL-23 is critical for the development of autoimmunity and for the generation of IL-17-producing Th cells [138e140]. 4.2. Induction and regulation of Th17 differentiation in human and mice Interestingly, IL-23 cannot induce Th17 differentiation, since naïve CD4þ T cells do not express IL-23R [140,141]. Rather, naive CD4þ T cells differentiate into Th17 cells in mice in the presence of TGFß1 and IL-6, which synergize to induce RORg expression via STAT3 activation. Although IL-6 can be replaced by IL-21, IL-6 is more potent. IL-21 favors an autocrine loop for Th17 cells and e together with TGFß eamplifies Th17 differentiation [42,71,72]. TGFß and IL-6/IL-21 induce surface expression of IL-23R, which makes Th17 cells IL-23-responsive (Fig. 4) [12,42,72,140,142]. Hereby, IL-23 is a critical factor for the stabilization and the pathogenic phenotype of Th17 cells via STAT4 [11,12,142,143]. In contrast to observations in mice [52], TGFß is indispensable for human Th17 differentiation. A combination of TGF-b, IL-1b and IL-6, IL-21 or IL-23 in serum-free conditions was necessary and sufficient to induce expression of IL-17 and RORg [144,145]. IL-1ß and IL-6 are important for Th17 cell expansion; IL-1R and IL-23R are not expressed on human naïve T cells, but induced by TGFß and IL6/IL-21 (Fig. 4) [144e147]. On the other hand, retinoic acid signaling via RARa and RARg has been shown to limit Th17 polarization (Fig. 4) [148]. IL-2 signaling via STAT5 also constrains Th17 polarization [149]. IFNg and IL-27 (via STAT1) as well as IL-12 (via STAT4) block Th17 differentiation by preventing activation of RORg. 4.3. Direct evidence for a role of Th17 cells in autoimmunity and host defense Th17 cells have been implicated in various autoimmune and infectious diseases. IL-17 was identified in lesions in MS, psoriasis,

€gren's syndrome and IBD [150e154]. In addition to GWAS RA, Sjo supporting an important role for Th17 cells (as discussed above), specific mutations linked the Th17 lineage to autoimmune disease. An uncommon IL-23R coding variant (R381Q) conferred strong protection against Crohn's disease, whereas several variants in noncoding regions of the IL23R gene were associated with increased susceptibility to various other autoimmune diseases [155e159]. Mutations in IL12RB1 (encoding the signal transduction chain of IL12R and IL-23R), RORC, IL17F, IL17RA or STAT3 lead to susceptibility to various bacterial and fungal infections [13,160e166]. 5. Th17 subset plasticity and autoimmunity 5.1. Th17 subpopulations and pathogenicity Th17 cells are highly heterogeneous in terms of trafficking receptors. Th17 cells from human tonsils express both Th1-associated (CCR2, CXCR3, CCR5 and CXCR6) and Th2-associated (CCR4) chemokine receptors. Like Tregs, they also express major nonlymphoid tissue trafficking receptors, such as CCR4, CCR5, CCR6, CXCR3, and CXCR6 [167]. Using combinations of chemokine receptors, RORCþCCR6þ Th17 or Th22 cells can be distinguished, as Th17 cells are CCR10- and Th22 cells are CCR10þ. It is becoming clear that CCR6þ Th17-lineage cells can be classified in four subpopulations: classical Th17 cells (CCR4þCXCR3-), so-called doublepositive cells (CCR4þCXCR3þ), non-classical Th17.1 cells (CCR4CXCR3þ) and double-negative cells (CCR4CXCR3-) [168], which differ in cytokine production and TF expression [169,170]. Classical CCR4þCXCR3-Th17 cells produce high levels of IL-17A, whereas CCR4CXCR3þ Th17.1 cells produce low amounts of IL17A but high levels of IFNg and express T-bet [16,170e172]. To date, Th17.1 cells have been identified in many autoimmune diseases, including RA, MS and IBD, both in peripheral blood and at sites of inflammation, as summarized in Table 1. Compared to classical Th17 cells, Th17.1 cells display a pathogenic signature that includes an increased ability to proliferate in response to TCR

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Fig. 4. Comprehensive overview of signals and nuclear factors driving Th17 differentiation and pathogenicity. Th17 cell function is shaped by numerous signaling pathways; see text for additional details. These pathways include signaling routes that 1) promote Th17 differentiation and non-pathogenic functions (light blue receptors, including PROCR [215] and PDPN [216] signaling but also intracellular metabolic control by CD5L), 2) inhibit Th17 development and/or expansion (light grey receptors, including MEK/ERK [217], retinoic acid and Vitamin D [218] signaling [219]) or 3) induce a phenotypic shift towards a pathogenic state (light red, including IL7R [220], PTGER2 [221,222] and Notch signaling [223]). Glucose transport via Glut1 is required for Th17 differentiation but can also promote pathogenicity [224]. It should be noted that the role of Notch signaling and the ligands involved is still controversial [225,226]. Non-pathogenic and pathogenic Th17 cells secrete common and distinct sets of soluble factors (listed in the lower left corner; CXCL3, CCL3, CCL4 and CLL5 are also known as GRO3, MIP-1a, MIP-1b and RANTES, respectively). Expressing of the various receptors and cytokine is driven by a set of common as well as statespecific TFs in the nucleus. TCR, T cell receptor; RA, retinoic acid; Vit.D, Vitamine D.

signaling high GM-CSF production, increased T-BET, STAT4 and RUNX expression as well as decreased IL-10 and AHR expression [170,173,174]. In particular, Th17.1 cells specifically upregulate multidrug resistance-1 (MDR1), an ATP-dependent membrane efflux pump, which provides resistance to glucocorticoid-mediated suppression [169]. It was shown in mice that pathogenic Th17 cells induce expression of various pro-inflammatory effector molecules, such as CXCL3, CCL4, CCL5, GM-CSF, IL-3, IL-22, Granzyme B, as well as the Th1-associated TFs T-bet and STAT4 [175]. Conversely, nonpathogenic Th17 cells manifest a gene signature that included expression of IL-10 together with TFs controlling IL-10 production (i.e. AHR, c-MAF and Aiolos (IKFZ3)), as well as IL-1R antagonist [175]. Accordingly, recent analysis of human peripheral blood revealed that IFN-gþ and IFN-g- Th17 cells display distinct transcriptional profiles, whereby IFN-gþ Th17 cells show elevated expression of pro-inflammatory cytokines and chemokines [176]. In this context, it is of note that Th17 heterogeneity is not limited to chemokine receptor, cytokine and TF expression, as recent single

cell RNA-Seq studies in EAE revealed several other types of genes governing pathogenicity and disease susceptibly [20,21]. These include the glycosphingolipid receptor Gpr65, genetic variants of which are associated with MS, ankylosing spondylitis and IBD [177e180]; the TF PLZP (also called ROG or ZBTB32) that represses GATA3 [181] in Th cells; and the Fc receptor for IgM TOSO (FAIM3), a surface molecule that negatively regulates Fas-mediated apoptosis [182]. By contrast, CD5L, a member of the scavenger receptor cysteine-rich superfamily, was found to be preferentially expressed in non-pathogenic Th17 cells [21]. CD5L acts as a functional regulator of Th17 cells by modulating the intracellular lipidome, thereby restricting ligand availability for RORg. 5.2. Th17 plasticity Th17 cells exhibit both instability (when they cease to express their signature cytokine IL-17A) and plasticity (when they start expressing cytokines typical of other lineages) upon in vitro restimulation [16,183]. Actual conversion of Th17 to Th17.1 cells was

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Table 1 Plasticity of Th17 cells in various autoimmune disorders. Autoimmune disease

Th17 Plasticity

Location

References

Diabetes type 1 (T1D)

IFNgþ Th17.1

[227e229]

Diabetes type 1 (T1D) Diabetes type 1 (T1D) Autoimmune uveitis and dry disease (DED) IBD

IL17þFOXP3þ IL-9þ Th17 IFNgþ Th17.1

Peripheral blood of children with type 1 diabetes and advanced b cell autoimmunity; islets and lymph nodes of NOD.Scid mice Peripheral blood of new-onset children with T1D Peripheral blood of patients with T1D Eyes from experimental DED or autoimmune uveitis mice

Juvenile idiopathic arthritis Multiple Sclerosis/EAE

IFNgþ Th17.1 IFNgþ Th17.1

Multiple Sclerosis/EAE

IL-9þ Th17 Th17/Tr1 IFNgþ Th17.1

Intestine of Crohn's disease patients; Colon of patients with ulcerative colitis; Colonic lamina propria in a colitis mouse model Peripheral blood of patients Peripheral blood or cerebrospinal fluid from MS patients; Lymph nodes and CNS from EAE mice Lymph nodes and EAE mice Lymph nodes from EAE mice Peripheral blood and synovial fluid of RA patients

IFNgþ Th17.1

Bronchoalveolar lavage and mediastinal lymph nodes of sarcoidosis patients Salivary glands of patients

RA Psoriasis Sarcoidosis €gren's disease Sjo

IFNgþ Th17.1

supported by the finding that stimulation of human Th17 clones with IL-12 in the presence or absence of IL-23 leads to the downregulation of RORg and IL-17 and upregulation of T-BET and IFNg [16,184]. These Th17-derived Th17.1 cells are CD161þ and linked to parameters of inflammation [185]. The development of IFNg-producing effector T cells from IL-17-producing cells is inhibited by TGFb1, which is important for the maintenance of IL-17 expression in Th17-polarized cells [17,186]. Cell fate tracing studies in mice established that IFNg and GMCSF expression in EAE is induced in cells that were originally Th17 cells [183]. Th17 cell plasticity towards IFNgþ Th cells was also prominent in intestinal Helicobacter hepaticus or Citrobacter rodentium infections, and in a Th17 transfer colitis model [187e189]. The strong propensity of Th17 cells to adopt a Th1 celllike profile suggests that plastic ex-Th17 cells are the main drivers of inflammation in tissue pathology [190]. Although Th17, FOXP3þ Treg and Tr1 cells are functionally distinct, they share several features: (i) they are abundant in the intestine, (ii) their differentiation is promoted by TGFß [191], and (iii) both Th17 and Tr1 cells express CD49b and high levels of the transcription factor AHR [192,193]. Moreover, Th17 cells can transiently co-express RORg with Foxp3 [194,195], and IL-17A with IL10 [18,196e198]. Under pro-inflammatory conditions in the gut, intestinal Th17 cells can differentiate into IL-10-producing Tr1-like cells, which depend on AHR and TGFß signaling [19]. In mice, Treg cells can be converted to IL-17-producing T cells [48,199,200]. Human Tregs were also reported to differentiate into IL-17-producing T cells, accompanied by upregulation of RORg and CCR6 expression [201]. Th17 cells originating from FOXP3þ T cells were shown to play a key role in the pathogenesis of autoimmune arthritis [202]. Finally, Tbx21 resides in an epigenetically primed state in both Th17 cell and Tregs [115]. Th17 cells can also adopt a functional profile of Tfh cells in Peyer's patches to support IgA class switching of GC B cells [203]. Under pro-inflammatory conditions in the gut, intestinal Th17 cells can transdifferentiate into IL-10-producing Tr1-like cells that depend on AHR and TGFß signaling [19]. Furthermore, both Th1 and Th17 cells can produce IL-4 during helminth infections in mice [204]. GATA3þRORgþ T cells that produce both IL-4 and IL-17 have been detected in the blood and bronchoalveolar lavage of asthmatics [205,206]. Evidence was presented that these T cells promote exacerbation of chronic allergic asthma and are associated with severe assthma and steroid resistance. Taken together, these observations strongly indicate that plasticity between Th17 cells and Th1, Th2, Tfh and Treg cell subsets

[230] [58] [231,232] [16,169,187,233] [185] [20,52,183,220,234e236] [59,60,235] [19] [172,237,238] [239e241] [242]

exists and that polarization does not completely restrict these subsets to separate lineages. It is currently unknown whether Th17 cell plasticity merely reflects a change in the expression of a few cytokine genes, or whether Th17 cells undergo complete global epigenetic reprogramming [207]. Importantly, although Th17 cell instability and plasticity has been associated with pathogenicity, it is conceivable that these aspects of Th17 biology also provide therapeutic opportunities, whereby previously pathogenic Th17 cells could be induced to adopt an anti-inflammatory fate. 6. Future perspectives Extensively studying Th17 cells has clearly revealed their important role in autoimmune disease pathogenesis and their strong dependence on triggers from the cellular environment, which crucially affects their phenotype and function. Future research will focus on the identification of the critical cellular and molecular differences that distinguish pathogenic from nonpathogenic Th17 cell populations in the context of autoimmune disease and host defense. Our technological repertoire for exploring cellular differentiation, heterogeneity and plasticity of Th17 is rapidly expanding. These include imaging techniques, such as multispectral, super-resolution and 3D-microscopy, as well as single-cell based genomics technology and mass cytometry (CyTOF), which are expected to contribute to the development of personalized medicine and to enhance discovery of cellular biomarkers that guide treatment of autoimmune disease patients [208]. Of particular interest are novel methods to profile gene expression or chromatin landscapes in single cells, which allow researchers to quantify heterogeneity within (rare) populations of immune cells, identify pathogenic cell populations and study plasticity in unprecedented detail [209]. Single cell RNASequencing has been employed to study Th17 cell heterogeneity in a mouse model of autoimmunity, resulting in the identification of new genes involved in pathogenicity and disease susceptibility (see above) [20]. Future studies applying single cell sequencing approaches on Th17 cell populations isolated from patient material are bound to yield valuable new insights into the biology of Th17 cells driving autoimmunity. Another interesting avenue to explore is the impact of 3D chromatin organization on epigenetic priming and T cell plasticity, which will require systematic and high-resolution analysis of genome topology during human Th cell differentiation. Future advances are also expected to come from analyzing even larger groups of autoimmune patients at the genetic

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level and including whole-exome or whole-genome sequencing to increase the probability of discovering novel rare variants. In addition, epigenome-wide association studies (EWAS) could be employed to look for epigenetic variation (e.g. differences in DNA methylation [210]) linked to autoimmune disorders. Functional validation of GWAS/EWAS hits will be of crucial importance, which is becoming increasingly feasible using advanced CRISPR-Cas9 and chromosome conformation capture methodology [129,211]. It may not be straightforward to translate the outcome of combined genetic and epigenetic studies into novel modalities to treat autoimmune disease. However, it is evident that the strength of these unbiased approaches is that they offer the possibility to identify genetic variants that functionally impact the expression of (immune) genes involved. In this context, super-enhancer elements are interesting in that they (i) control core cell identity genes, (ii) contain major disease-associated genetic variants and (iii) are remarkably vulnerable to inhibitors of transcriptional activation. Therefore, the use of ‘epigenetic drugs’ that interfere with epigenetic mechanisms, such as DNA methylation and histone modifications, could potentially alter disease-related gene expression by inducing transcriptional activation or silencing [212]. Although side effects of such drugs could pose a problem, we predict that the near future is likely to yield epigenetic drugs with increased sensitivity and specificity, providing valid novel treatment strategies for autoimmune disease.

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These studies were partially supported by an NWO Veni Fellowship (Grant No. 91617114) to R.S.

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Please cite this article in press as: R. Stadhouders, et al., A cellular and molecular view of T helper 17 cell plasticity in autoimmunity, Journal of Autoimmunity (2017), https://doi.org/10.1016/j.jaut.2017.12.007