Th17 Cells in autoimmune diseases

Abstract

Th17 cells are a new subset of CD4⁺ T cells involved in the clearance of extracellular pathogens and fungi. Accumulating evidence suggests that Th17 cells and their signature cytokines have a pivotal role in the pathogenesis of multiple autoimmune-mediated inflammatory diseases. Here, we summarize recent research progress on Th17 function in the development and pathogenesis of autoimmune diseases. We also propose to identify new small molecule compounds to manipulate Th17 function for potential therapeutic application to treat human autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, inflammatory bowel disease, and multiple sclerosis.

Keywords

IL-17 / Th17 cells / RORγt / autoimmune diseases / posttranslational modification / inhibitors

Introduction

Th17 cells have been identified as a new CD4⁺ T helper lymphocyte lineage following the promising discovery of the role of IL-23 in experimental autoimmune encephalomyelitis (EAE) [ 1] and collagen-induced arthritis (CIA) [ 2]. They are characterized according to their capacity to produce interleukin (IL)-17A (also called IL-17), IL-17F, and IL-22 [ 3]. Th17 cells are currently assumed to mediate host defense, especially against extracellular bacterial infections, and play an important role in the pathogenesis of autoimmune diseases [ 4]. In this review, we discuss our current understanding of the role of Th17 cells in autoimmune diseases, with a focus on rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), inflammatory bowel disease (IBD), and multiple sclerosis (MS).

Th17 cells

Naïve CD4⁺ T cells differentiate into diverse subsets of T helper cells depending on different cytokine milieu upon T-cell receptor (TCR) stimulation. Unlike the required cytokines for Th1 and Th2 differentiation, the combination of transforming growth factor-β (TGF-β) and IL-6 initiates the development of Th17 lineage in mice [ 5, 6]. TGF-β favors the induction of Th17 under inflammatory milieu despite its role in the development of regulatory T cells [ 7]. IL-6 induces the production of IL-21, which subsequently amplifies the differentiation in an autocrine way [ 8]. IL-23 stabilizes the Th17 phenotype and maintains its ability to produce related cytokines [ 9]. By contrast, the role of TGF-β in the differentiation of human Th17 cells is controversial. Previous research suggested that human Th17 cells were induced by IL-1β plus IL-6 and suppressed by TGF-β [ 10]. More recent studies show that a combination of TGF-β, IL-1β, IL-6, and IL-23 is critical for human Th17 development [ 11, 12].

The retinoic acid-related orphan receptor γt (RORγt), as the master transcription factor, orchestrates the differentiation of Th17 cells [ 13]. RORγt directs the transcription of IL-17A by directly binding to the IL-17A promoter, which is essential for the functions of this cell lineage [ 14]. Moreover, another related nuclear receptor RORα cooperates with RORγt to trigger greater Th17 response and upregulates the expression of IL-17A and IL-17F [ 15]. Moreover, other key transcription factors, including signal transducer and activator of transcription 3 (STAT3), interferon regulatory factor 4 (IRF4), and aryl hydrocarbon receptor (Ahr), have been identified as the pivotal factors during the differentiation and function of Th17 cells [ 16– 18].

The key effector cytokine of Th17 cells is IL-17A [ 9]. The IL-17/IL-17R complex recruits the U-box-like E3 ubiquitin ligase Act1 to trigger intracellular signaling pathways through homotypic interactions. Binding of Act1 to tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TGF-β-associated kinase 1 (TAK1) ultimately activates the canonical NF-κB pathway [ 19]. However, not all the Th17 are pathogenic; thus, TGF-β3 and IL-6 are attributed to the full pathogenic phenotype, which is IL-23 dependent [ 20].

Th17 and RA

RA is an autoimmune rheumatic disease characterized by inflammation of multiple joints, which eventually leads to progressive joint destruction and deformity. Immune cells infiltrate the synovium of RA following aberrant cytokine and chemokine signaling [ 21].

IL-17A cytokines are involved in the pathogenesis of RA, which has been well established both in animal models of autoimmune arthritis and RA patients. IL-17A has been detected both in the serum and synovial fluid (SF) of RA patients [ 22– 24]. IL-17A induces the expression of receptor activator of the nuclear factor kappa B ligand (RANKL) to enhance osteoclastogenesis [ 25]. Anti-IL-17A treatment reduces the expression of RANKL, alleviates bone structural damage, and reduces disease progression in models [ 26]. Moreover, antibodies against IL-17A, such as secukinumab, have already been used in clinical trials [ 27, 28]. Enhanced epigenetic modifications in RA patients lead to the production of IL-17A, which sustains the survival of synoviocytes and inflammatory cells. These effects initiate the expansion of Th17 cells [ 21]. However, mast cells were also found as the main producer of IL-17A in the synovial tissue of RA patients in a clinical study [ 23].

IL-17F, another Th17-specific cytokine, was significantly increased in RA patients versus healthy control. IL-17F, but not IL-17A, was reduced after methotrexate and anti-TNF treatment [ 29]. This result indirectly proved the role of Th17 cells in the development of RA. Spontaneous development of autoimmune arthritis in SKG mice, which resembles RA in humans, is accompanied with enhanced arthritogenic Th17 cells [ 30]. Higher frequencies of Th17 cells are observed in RA patients as compared with those from healthy groups [ 31– 36] (Table 1). Th17 frequencies in RA SF mononuclear cells (SFMC) are higher than paired RA peripheral blood mononuclear cells (PBMC) [ 37]. Moreover, CCR6⁺ memory Th17 cells from early RA patients trigger pathogenic activation of RASFs, which elevates the production of proinflammatory cytokines and other relevant enzymes [ 33]. Interestingly, the frequency of Th17 cells in RA joints is low, which suggests that Th17 cells might not be the main producer of IL-17A within RA joints [ 37]. This finding might be explained by the proposal that Th17 cells are unstable and spontaneously convert to a Th1 phenotype [ 38]. The adoptive transfer of polarized Th17 cells induces severe, destructive polyarthritis in mice, and IL-17A produced by Th17 cells is attributed to the osteoclastogenic effects of Th17 cells [ 39]. In addition, Th17 cells could assist the B cell in producing autoantibodies [ 40]. A small fraction of Th17 cell lineage, which originates from CD25^loFoxp3⁺CD4⁺ T cells, possesses more potent osteoclastogenic capability than conventional Th17 cells under arthritic conditions [ 41].

Th17 and SLE

SLE is a chronic systemic autoimmune disease characterized by dysregulation of the immune system, which leads to loss of self-tolerance with activation of autoreactive T and B cells [ 42]. Production of autoantibodies contributes to deposition of immune complexes and tissue injury.

In the past years, numerous studies have reported elevated serum IL-17A levels in SLE patients compared with healthy controls [ 43– 46]. However, a weak correlation was found between IL-17A levels and SLE disease activity index (SLEDAI) [ 46]. Moreover, IL-17A-deficient mice are prevented from the induction of SLE by pristane [ 47], which suggested that IL-17A contributes to the pathogenesis of SLE. Consistent with the increasing serum IL-17A, expansion of Th17 population in SLE patients is also observed and correlated with SLEDAI in most studies (Table 2). One study indicated that Th17 cells in lupus nephritis (LN) patients were higher than those in conventional SLE patients [ 48]. Th17 cells were suggested as a predominant resource of IL-17A in SLE patients in a clinical study [ 49].

However, the alteration of IL-17A levels and Th17 cell frequencies has not been confirmed in larger groups. In the peripheral blood of SLE patients, data about the source of IL-17A are inconclusive, with several studies reporting the importance of CD3⁺CD4^–CD8^– double-negative (DN) T cells (expressed as either αβ- or γδ-TCR). In patients with SLE, the capacity of IL-17A production by activated CD4⁺ T cells was equal to that observed in DN T cells. These IL-17A-producing TCRαβ⁺ DN T cells are detected in kidney biopsies of LN patients [ 50]. Furthermore, reduced frequency of DN T cells (not mentioned as either TCRαβ⁺ or γδ⁺) was observed in IL-17A-deficient mice, which were protected from the induction of SLE by pristane [ 47]. IL-2 mitigates inflammation in MRL/lpr mice by reducing IL-17A-producing TCRαβ⁺ DN T cell [ 51]. By contrast, rapamycin inhibits IL-17A production most in CD4⁺ T cells [ 49]. Above all, the role of Th17 in SLE needs to be investigated further.

Th17 and SS

Primary SS is an autoimmune disease primarily characterized by chronic inflammation of exocrine glands, which leads to glandular atrophy and deficient function [ 57, 58]. The infiltration of lymphocytes is mainly responsible for the inflammation, and CD4⁺ T cells constitute the majority of infiltrating lymphocytes in the salivary glands [ 59, 60].

IL-17A knockout (KO) mice are resistant to the induction of SS. Adoptive transfer of Th17 cells into the inducible IL-17A KO mice could rapidly acquire a SS profile [ 61]. C57BL/6J mice that receive adenovirus serotype 5 (Ad5) -IL17A vector, an SS model, express high levels of IL-17A, which correlates with recruitment of inflammatory cells [ 62]. In patients with Sjögren’s syndrome, both systematically elevated levels of IL-17 [ 63, 64] and presence of Th17 cells [ 65– 67] in inflamed tissue have been observed in multiple studies. Th17 cells are also observed as the predominant infiltrating T cells in the salivary glands [ 65]. High levels of IL-7 secreted from SS patients have the potential to promote Th17 polarization [ 59]. Furthermore, Th17 cells are hypothesized to promote the generation of germinal centers and function as B-cell helpers [ 68]. This evidence indicates the role of Th17 cells in the pathogenesis of Sjögren’s syndrome.

CD3⁺CD4^–CD8^– DN T cells (either TCRαβ⁺ or γδ⁺) were reportedly a predominant producer of IL-17A in SS and infiltrated the salivary gland of SS patients, and TCRαβ⁺ DN T cells were associated with disease progression [ 69]. Circulating DN T cells are not expanded and inversely correlated with Th17 cells in the early stage of SS. In addition, minor salivary gland infiltrating DN T cells are inversely correlated with circulating DN T cells [ 70]. These results might support the hypothesis that DN T cells might derive from Th17 cells and acquire the ability to migrate into the salivary glands continuously in early SS. Furthermore, IL-17A⁺ DN T cells from SS were almost resistant to dexamethasone (Dex) treatment, while Dex was capable of significantly reducing IL-17A production from activated CD4⁺ T cells [ 69]; this condition might be the reason for the poor response of SS patients to common Dex treatment.

Overall, the following hypothesis is developed according to the above evidence: Th17 cells and their production are mainly involved in the initiation of SS. Subsequently, Th17 cells lose expression of surface molecules and give rise to the DN T cell upon the chronic inflammatory milieu. Finally, these IL-17A-producing DN T cells infiltrate the target glands and promote glandular damage.

Th17 and IBD

IBDs, including ulcerative colitis (UC) and Crohn’s disease, are chronic relapsing inflammatory diseases that mainly destroy the gastrointestinal tract [ 71]. The etiology of IBD remains unclear.

Before the discovery of Th17 cells, the Th1/Th2 paradigm was considered critical for mediating mucosal inflammation [ 72]. The main mechanism of UC was thought to be a Th2 response, while CD was thought to be caused by Th1 cells [ 73]. Recently, higher levels of IL-17A and IL-17F have been observed both in IBD mucosa and lamina propria compared with those in a normal gut [ 74, 75]. Massive infiltration of Th17 cells was also detected in IBD patients [ 76]. Based on the accumulating evidence, Th17 cells also contribute to the pathogenesis of IBD and show more potent capacity than Th1 cells in the induction of colitis [ 77]. This finding might be explained by the conversion of Th17 cells to Th1 cells via induction of mucosal IL-23 production in IBD patients [ 77]. Consistent with the aforementioned results, several genes involved in Th17 signaling, such as IL23R and STAT3, could confer susceptibility to IBD, according to the analysis by genome-wide association studies [ 78]. A monoclonal antibody against TNF infliximab downregulates IL-17A expression, which is one of the mechanisms by which infliximab alleviates IBD-related mucosal inflammation [ 79]. IL-21, a cytokine produced by Th17 cells, is upregulated in inflamed mucosal tissue [ 80].

However, confusing results on dextran sulfate sodium-induced colitis revealed that IL-17A deficiency exacerbates colitis, whereas a lack of IL-17F alleviates colitis in mice [ 81]. Adoptive transfer of CD45RB^hi T cells from IL-17A-knockout mice induces a more aggressive colitis, which has higher IFN-γ expression [ 82]. By contrast, IL-17RA-deficient mice develop mild colitis [ 83]. These results support the finding that Th17 cytokine can also have protective functions in the intestine and that the pathogenic effect is mainly IL-17F mediated [ 84]. Sarra et al. proposed that whether Th17 cells were inflammatory or protective would depend on the cytokine milieu, especially IFN-γ [ 85]; it could also be explained by the existence of ex-Th17 cells, a type of Th17 cells that was found in Helicobacter hepaticus (Hh)-induced intestinal inflammation. In Hh-induced colitis, CD4⁺ T cells differentiated into Th1 and Th17 cells, and IL-17A⁺ cells partly turned into IFN-γ⁺ IL-17A⁺ cells, then became IFN-γ⁺ ex-Th17 cells [ 86]. IL-23 has been confirmed as a key driver in this process [ 87]. Moreover, anti-IL-17A antibody secukinumab failed to attenuate clinical activity in CD patients [ 88]. In conclusion, how Th17 exert functions in the intestinal inflammation needs further investigation.

Th17 and MS

MS is a progressive autoimmune-mediated inflammation of the central nervous system (CNS), and its pathological feature is demuelination, which ultimately leads to neurological impairment [ 89]. The pathogenic mechanisms are widely explored through EAE in mice, which resembles MS in humans.

Over the past decades, EAE induction has been demonstrated to be dominated by Th1 cells [ 90]. Th1 and Th17 cells are identified as the encephalitogenic mediators in MS and its mice models with the discovery of IL-23 [ 3]. However, determining which cell has the dominant role in the pathogenesis of MS remains a controversial topic [ 91, 92]. Increased frequencies of circulating Th17 cells and serum IL-17A have been observed in MS [ 93, 94]. Moreover, in vitro differentiation of myelin oligodendrocyte glycoprotein-specific Th17 cells could induce EAE. Certain costimulatory pathways have also been demonstrated to restrain EAE development by suppressing the generation of Th17 cells and their infiltration into the CNS [ 95].

Nevertheless, none of the Th17 signature cytokines have been identified as the indispensable component for the development of EAE [ 96– 98]. Only when cultured with IL-23 could Th17 recipients exert inflammatory functions by inducing ectopic accumulation of lymphocytes [ 92]. Deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) in autoreactive Th cells is resistant to the induction of EAE despite the presence of IL-17A or interferon (IFN)-γ [ 99]. Encephalitogenic GM-CSF also contributes to the maintenance of the Th17 phenotype [ 100]. Furthermore, a high-salt diet leads to a more severe form of EAE in mice, which are accompanied with a highly pathogenic Th17 population. These pathogenic Th17 cells could upregulate the expression of proinflammatory cytokines, such as TNF-α, IL-2, and GM-CSF [ 101]. Overall, the aforementioned results indicate that Th17 cells might exert their encephalitogenic capacity mainly through GM-CSF and other molecules [ 102] but not classical Th17 signature cytokines.

Treatment against Th17 cells in autoimmune diseases

On account of the Th17 cell pathogenicity in autoimmune diseases, extensive research efforts focus on investigating therapeutic strategies against Th17 cells. The relevant mechanisms that target Th17 cells are faced with an obstacle to achieving differentiation and amplification of the Th17 cell, neutralization of Th17 signature cytokines, and inhibition of the Th17-specific transcription factor [ 103]. Ustekinumab [ 104, 105], which targets the IL-12/IL-23 pathway, or anti-IL-17A monoclonal antibodies AIN457 [ 106], LY2439821 [ 107], and secukinumab [ 88] have shown promising therapeutic effects for the treatment of autoimmune diseases, such as RA, psoriasis, and CD. Nevertheless, the high cost of the monoclonal antibody has to be taken into consideration because the majority of patients could not afford it. Therefore, effective small molecule compounds should be investigated.

RORγt plays a central role in the development and function of Th17 cells. Therefore, RORγt would be a potential pharmacologic target for the treatment. Based on a small molecule screen, several RORγt inhibitors are identified, including digoxin, ML209, SR1001, SR2211, and ursolic acid [ 108]. Treating animals with these small molecules not only delays the onset but also alleviates the severity of models of EAE and CIA [ 109– 112]. Recently, TMP778, TM920, and GSK805, which were screened from a benzhydryl amide group, have been identified as highly potent and selective RORγt inhibitors [ 113]. Moreover, TMP778 and GSK805 ameliorate the progression of EAE dramatically by inhibiting Th17 cell generation. AS101 (trichloro (dioxoethylene-O, O′) tellurate), an organotellurium compound, has been found to be able to alleviate the progression of EAE by blocking the activation of STAT3 and RORγt [ 114]. All these inhibitors and their derivatives might be used as therapeutic agents that treat autoimmune-mediated inflammatory diseases.

Targeting other modulators of RORγt, such as deubiquitinases, could be a novel strategy for the treatment of autoimmune diseases. The deubiquitinases have been indicated as important modulators in Th17 cells. For example, deficiency of ubiquitin-specific protease 25 (USP25) exacerbates the severity of EAE by enhancing IL-17A-mediated responses [ 115]. Moreover, we have recently identified deubiquitinase USP17 as a novel regulator of RORγt [ 116]. USP17 affects the functions of Th17 cells by stabilizing RORγt via deubiquitination. Furthermore, USP17 level is increased in SLE patients. Based on the potential application of deubiquitinase inhibitors in cancer therapy [ 117], further efforts need to be explored to test whether these inhibitors could also have therapeutic applications in the treatment of autoimmune diseases.

Conclusions

The function of Th17 cells has proven to be indispensable for the development of autoimmune diseases. However, Th17 cells obviously exert pathogenic capacity through multiple molecular pathways in each specific autoimmune disease. Numerous unresolved scientific questions need to be investigated in the development and function of Th17 cells in health and disease. An enhanced understanding of Th17 functions in autoimmunity could promote more effective therapies in clinical practice.

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