Th17 cells in inflammation and autoimmunity Ram Pyare Singh, Sascha Hasan, Sherven Sharma, Saranpreet Nagra, Dean T. Yamaguchi, David Wong, Hahn BH, Awlad Hossain PII: DOI: Reference:

S1568-9972(14)00163-3 doi: 10.1016/j.autrev.2014.08.019 AUTREV 1592

To appear in:

Autoimmunity Reviews

Received date: Accepted date:

18 June 2014 5 July 2014

Please cite this article as: Singh Ram Pyare, Hasan Sascha, Sharma Sherven, Nagra Saranpreet, Yamaguchi Dean T., Wong David, BH Hahn, Hossain Awlad, Th17 cells in inflammation and autoimmunity, Autoimmunity Reviews (2014), doi: 10.1016/j.autrev.2014.08.019

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT 1 Th17 cells in inflammation and autoimmunity Ram Pyare Singha,

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, Sascha Hasanb, Sherven Sharma,c Saranpreet Nagra a, Dean T

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Yamaguchi c, David Wong,d Hahn BHa and Awlad Hossaina

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Division of Rheumatology a, Sanguine Biosciences Inc b, Research Service, Veterans Affairs Greater Los Angeles Health Care System c and UCLA School of Dentistry d at the David Geffen

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School of Medicine, University of California Los Angeles, CA, 90095-1670

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Running Title: The role of Th17 in inflammation and autoimmunity

Keywords: Th17, Sex Hormones, Autoimmunity, Systemic Lupus Erythematosus, Cancer,

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Mesenchymal Stem Cells

Supported by NIH grants AR54034, AI 083894, AI65645 to RPS, UCLA Senate Core Grant to BHH and RPS, UCLA Oppenheimer Clinical Seed Grant and American Autoimmune Related Disease Association and the Lupus Foundation of America Awards to RPS, VA Merit Review Award 2I01 BX000170-05 to DTY. a

To whom correspondence may be addressed. E-mail: [email protected]

ACCEPTED MANUSCRIPT 2 Abstract: T helper 17 (Th17), a distinct subset of CD4+ T cells with IL-17 as their major cytokine,

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orchestrate the pathogenesis of inflammatory and autoimmune diseases. Dysregulated Th17 cells contribute to inflammatory and autoimmune diseases. Candidate biologics are in

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development for targeting IL-17, IL-17 receptors or IL-17 pathways. Several drugs that impact

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the IL-17 pathway are already in clinical trials for the treatment of autoimmune diseases. In this

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review we provide evidence for the role of Th17 cells in immune-mediated diseases. An understanding of the role of Th17 in these conditions will provide important insights and unravel

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novel targets for therapeutic intervention.

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Take- home messages

Th17 cells modulate inflammation and autoimmunity.

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Estrogen regulates Th17 cells and participates in the pathogenesis of autoimmune

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diseases.

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Potential links between RA, SLE, MS and Th17 cells have emerged.

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Mesenchymal stem cells regulate Th17 cells in a dose and time-dependent manner in inflammatory/autoimmune disease.

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Understanding the cellular and molecular interactions of Th17 cells in disease states will provide novel therapeutic approaches for the treatment of inflammatory and autoimmune diseases.

ACCEPTED MANUSCRIPT 3 Introduction: Th17 cells are of central interest in the field of autoimmunity. There is accumulating evidence

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that Th17 cells regulate inflammatory and autoimmune diseases. The name Th17 is based on the ability of T helper cell subset to produce interleukin-17 (IL-17), primarily IL-17A and IL-17F

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[1]. IL-17 is a proinflammatory cytokine which induces other cytokines, chemokines, and

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prostaglandins. It has six known family members, 17A-F, that are expressed by innate and adaptive cells including neutrophils, natural killer cells, mast cells, invariant natural killer cells,

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as smooth muscle cells and epithelial cells.

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paneth cells, lymphoid-tissue inducer-like cells, Yδ and αβ T cells (both CD4+ and CD8+) as well

Th17 cells are a unique subset of CD4+ T cells, distinct from Th1, Th2, Foxp3+ T regulatory

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(Treg) cells, Th9, and Th22 cells [1-3]. The cytokines IL-6 and TGF- [4] as well as IL-21 and IL-23 [5-7] promote the differentiation of Th cells into mature Th17 cells through the activation of Two transcription factors, retinoic acid-related orphan

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Smad family proteins and STAT3.

receptor -t (ROR-t) [8] and RA-related orphan receptor α (RORα) [9], are necessary for Th17 differentiation. Together with p-Stat3, ROR-t and RORα induce the expression of Th17associated cytokines such as IL-17A, IL-17F, IL-21, IL-22 and IL-23 [10]. CD4+ Treg cells are also involved in the differentiation of Th17 cells. In the presence of IL-6 and TGF, naive CD4+ CD25- Foxp3- T cells promote Th cell differentiation into Th17 cells [11]. These studies show the crucial requirement of IL-6 for the differentiation of naïve CD4+ T cells into Th17 cells that is further enhanced by interleukin-1 (IL-1) and IL-23 [12]. It has also been shown that in the absence of exogenous TGF-, Treg cells can self- induce differentiation into Th17 cells. A recent study has demonstrated that IL-1 signaling in T cells is critical for the early programming of the Th17 cell lineage and Th17 cell-mediated autoimmunity. IL-1 synergizes with IL-6 and IL23 to regulate Th17 cell differentiation in a manner that is similar in humans and mice [13].

ACCEPTED MANUSCRIPT 4 The differentiation of CD4+Treg into Th17 cells in humans is controlled by the expression of IL1β and IL-2. Dendritic cells activated by dectin-1 convert CD4+T reg cells into Th17 precursors

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[14]. Within the Foxp3+T cells, only Foxp3+ROR-+T cells, but not Foxp3+ROR--T cells, become Foxp3+IL-17+T cells. These results indicate that some Foxp3+T cells can produce IL-17 while

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retaining Foxp3 expression, further suggesting that CD4+Treg cells can play an unanticipated

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pro-inflammatory role. Work by several groups has demonstrated that Th17 cells are also important in protecting the host against bacteria and fungal infections [15-20]. Th17 cells thus

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act as a double-edged sword in infection and autoimmunity. In cancer, Th17 cells have been

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shown to promote as well as inhibit the progression of tumors demonstrating that these cells have a broad significance in inflammatory diseases. In this review we will elaborate on the role of Th17 cells in autoimmunity (rheumatoid arthritis, encephalomyelitis, multiple sclerosis,

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systemic lupus erythematosus, psoriasis, type 1 diabetes, Sjogren syndrome, Crohn’s disease, asthma) and cancer. In addition, the maintenance and homeostatic regulation of Th17 cells by

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estrogen will be discussed.

Th17 and inflammation: Multiple studies have demonstrated the link between Th17 cells and inflammation. Cytokines expressed by Th17 cells play a role in the pathogenesis of inflammatory diseases. For example, IL-17 is over expressed in inflamed lung endothelial cells [21], in rheumatoid arthritis (RA), and in systemic lupus erythematosus (SLE) patient serum samples. IL-17 is also associated with skin inflammation [22]. IL-17 consists of a family of proinflammatory cytokines that include: IL-17A-F [23]. The action of IL-17 is mediated through IL-17 receptors A-F of which IL-17A is the most common. Thus IL-17A neutralizing antibodies have the potential to treat autoimmune diseases in humans.

Another cytokine IL-23, a major driver of inflammation, is involved in the maintenance of Th17 cells [24]. In Crohn’s disease, IL-23 promotes inflammation.[25]. In inflammatory conditions, IL-

ACCEPTED MANUSCRIPT 5 23 promotes T cells to produce IL-17 and IL-6 [26]. Another cytokine, IL-22 has been shown to play an important role in the pathogenesis of autoimmune diseases like rheumatoid arthritis

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(RA). Interleukin-22 (IL-22) is a member of the IL-10 family of cytokines that is produced by different subsets of lymphocytes including Th17 cells. IL-22 mediates its effects through the IL-

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22- IL-22R complex and the subsequent Janus kinase-signal transducer and activators of

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transcription, ultimately activating the (JAK-STAT) signaling pathway [27]. In cancer studies, expression of IL-22 leads to tumor growth, inhibition of apoptosis and promotion of metastasis

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by STAT3 activation [28].

Th17 cells secrete several chemokines at the site of inflammation. For example the expression of CCL20 and CCR6 by Th17 cells promotes recruitment of Treg cells and Th17 cells to the

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inflammatory sites. Th17 cells express CCR6 at chronic inflammatory sites and neutralization of CCL20 and CCR6 interaction decreases the susceptibility to experimental autoimmune

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encephalomyelitis (EAE) in mouse models [29]. On the other hand, p38 MAP kinase (MAPK), has been shown to regulate IL-17 synthesis and production in CD4+ T cells through the activation of the eukaryotic translation initiation factor 4E/MAPK-interacting kinase (eIF4E/MNK) pathway [30]. The alternative activation of p38 by T cells has been demonstrated to be important in Th cell skewing, pathogenesis of inflammation and autoimmunity [31].

Th17 and autoimmunity: Th17 cells and the expression of their related cytokines have been demonstrated in autoimmune diseases. A down regulation of Th17 cells reduces inflammation and autoimmune disease. For example in addition to negatively regulating Th17 cell differentiation, IL-27 suppresses severe inflammation of the immune system [32]. In addition IL17(-/-) mice exhibit suppressed encephalomyelitis and multiple sclerosis [33] that could be explained by IL-17 co-acting with B-cell-activating factor (BAFF) to promote B-cell differentiation and autoantibody production [34]. Consistent with this observation, in IL-9(-/-) EAE mice, IL-9

ACCEPTED MANUSCRIPT 6 deficiency correlates with the absence of IL-17 and IFN-γ expression within the central nervous system (CNS) and reduced susceptibility to EAE. Furthermore, IL-9 deficiency down regulates

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Th17 cells through STAT1 and STAT3 [35]. The ratio of Th17 cells to Th1 cells plays an important role in inflammation in the CNS. A disproportionate ratio of Th17/Th1 cells in the

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CNS, caused by infiltrating T cells, with Th17 cells outnumbering Th1 cells, leads to an increase

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of IL-17 levels and brain parenchyma inflammation [36]. Infiltration of Th17 in the CNS and release of IL-17 has also been implicated in the pathogenesis of multiple sclerosis (MS) [37].

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The ratio of Th17/Th1 cells is also important in bone maintenance. In comparison to Th1 cells,

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Th17 cells play an opposite role in bone breakdown and formation [38]. In addition, Th17 cells are involved in the pathogenesis of IBD (inflammatory bowel disease) [39] and MS that has therapeutic implications [40]. Similarly, Th17 and Treg cells have been shown to contribute to

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loss of tolerance in myasthenia gravis patients [41-43]. Thus the regulation of Th17/T reg cells plays an important role in deciding whether inflammation is sustained or resolved [44]. The

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environment also plays an important role on the immunoregulation of Th17 and T reg cells in the development of autoimmune diseases ([45]. For example in fibrotic autoimmune diseases such as primary biliary cirrhosis (PBC) and systemic sclerosis (SSc) an altered balance between effector and Treg cell circuits exist [46]. A further understanding of the mechanistic role of Th17 in inflammatory and autoimmune diseases will shed light on therapeutic targets that can potentially be exploited for the management of inflammatory and autoimmune diseases.

Role of Th17 in Rheumatoid Arthritis: The frequency of Th17 cells is higher in patients with rheumatoid arthritis (RA) than in healthy controls, suggesting that a Th17 cells/Treg imbalance may contribute to the pathogenesis and progression of RA [47]. In this disease, Th17 cells represent a pro-inflammatory subset whereas Treg cells have an antagonistic effect. Restoring Th17/Treg balance with specific receptors or signaling pathway drugs will provide unique therapeutic opportunities [48]. Studies demonstrate that IL-17 upregulates the production of IL-

ACCEPTED MANUSCRIPT 7 1β and TNFα in antigen presenting cells (APCs) in arthritic joints [49]. In RA patients synovial fluid has been shown to have high levels of IL-17 [50]. However in collagen induced arthritis

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(CIA) models treatment with neutralizing IL-17 monoclonal antibodies ameliorates joint inflammation [51]. Blockade of TNFα and IL-17 has a synergistic effect on the suppression of IL-

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6 production and degradation of collagen in RA patient synovium and bone [49]. As shown in

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another study, celastrol had significant anti-inflammatory, anti-Th17, and anti-proliferative properties in a rat model of adjuvant-induced arthritis (AIA) [52].

In a clinical study, IL-17

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neutralizing therapy ameliorated inflammatory cascades within peripheral synovial joints in

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patients with active RA. [53]. Similarly IL-17 and Th17 have a role in Behcet's disease (BD) and in uveitis patients [54], demonstrating that Th17 cells participate in the pathogenesis of

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autoimmune diseases.

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Role of Th17 in Systemic Lupus Erythematous: Systematic lupus erythematosus (SLE) is a

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complex autoimmune disease of unknown etiology. However multiple links between SLE and Th17 have emerged [55]. For example when SLE patients were evaluated for CCR4 and CCR6 expression, which is associated with CD4+ T cells producing IL-17, an increased frequency of the receptors was observed in patients with SLE in comparison to controls [56]. A strong correlation between Th17 cell expression and SLE disease activity with a higher percent of CD3+CD4-T cells producing IL-17 exists in SLE patients compared to healthy controls [57]. IL22, another Th17 cell cytokine, has a strong correlation with disease activity in SLE patients [58]. In addition the number of Th17 cells is higher in lupus-prone mouse models, including BXD2, SNF1, NZBxNZW F1 and Ro52 knockout mice [59-61]. mRNA levels of the Th17 cellrelated cytokines IL-17, IL-23, and IL-27 were found to be higher in the urinary sediment of patients with SLE. This upregulated cytokine signature inversely correlated with the expression of Th1 genes [62].

Collectively these studies demonstrate that Th17 cells play an important

role in the pathogenesis of SLE.

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Th17 in Sjogren Syndrome (SS): IL-17 and IL-23 levels are increased in the salivary gland as

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well as in the serum of patients with SS. In addition, these cytokines and their receptors were shown to be expressed within lymphocytic infiltrates and ductal areas in salivary glands of

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patients [63-67]. Moreover there is evidence of IL-17 having a crucial pathogenic role, and thus

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may serve as a potential therapeutic target for amelioration of SS. On the one hand, inhibition of IL-17 activity inhibits the development of SS-like disease in C57BL/6.NOD-Aec1Aec2 mice [68],

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while over expression of IL-17 in non-SS prone C57BL/6 mice induces SS-like disease

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symptoms such as tissue-inflammation and antinuclear autoantibody production [68]. In SS patients IL-22 may also have a role in the development of the disease in that its serum levels are increased and correlate with levels of autoantibodies and rheumatoid factor [69]. In addition

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SS patient salivary glands express increased levels of IL-22 mRNA and protein with Th17 and NK cells as the primary source of the cytokine [70]. Taken together these findings suggest a

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potential role of Th17 cells in SS pathogenesis.

Th17 in Psoriasis: Psoriasis is a chronic inflammatory skin disease of unknown etiology. In this disease, Th17 cells have received interest following the observation of increased numbers of circulating Th17 cells as well as cutaneous Th17 cells in lesions compared to non-lesion skin [71, 72]. Further, Th17 cells have been detected in dermal infiltrates of psoriatic lesions as well as in synovial fluid. [73]. Increased serum levels of IL-17 and IL-22 correlate with disease severity in psoriasis patients [74]. In these patients IL-17 induces the expression of antimicrobial peptides such as psoriasin, koebnerisin, β-defensin 2, S100A8, and S100A9 [74]. In addition IL17 upregulates the expression of neutrophil chemoattractants CXCL1, CXCL3, CXCL5, CXCL6, and CXCL8 which are angiogenic chemokines that could account for the increased vascularity seen in psoriatic lesions [74]. In addition, psoriasis is linked to a higher risk for cardiovascular

ACCEPTED MANUSCRIPT 9 diseases. Patients with elevated IL-17A appear to be at the highest risk for developing and

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dying from cardiovascular complications including stroke and myocardial infarction [75].

Th17 in Type 1 Diabetes: Type 1 Diabetes (T1D) involves CD4+ and CD8+ T-cell-mediated

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destruction of pancreatic β cells and uncontrolled expansion of Th17 cells is involved in T1D

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pathology of the disease [76]. Certain Treg cells malfunction in T1D and lose their ability to control Th17 cell development. The altered function of antigen-presenting cells (APCs) and a

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subset of monocytes that spontaneously releases IL-1 and IL-6 in T1D patients determine the

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uncontrolled expansion of Th17 cells. Consequently the pathogenic Th17 cells can lead to an imbalance between T-effector (Teff) and Treg cells [76] exacerbating T1D.

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Th17 in Asthma: In patients with allergic asthma the number of Th17 cells in peripheral blood, sputum, and bronchoalveolar lavage fluids is increased compared to healthy controls, and levels

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of Th17 cells positively correlate with the severity of airway remodeling [77, 78]. Contrary to Th17 cell levels, the number of Treg cells is decreased in asthma patients compared to controls [78]. In line with these observations, IL-17-induced neutrophilic penetration into the airways is prominent in severe asthmatic conditions. Furthermore, IL-17 mRNA expression level is increased in the sputum of asthma patients compared to controls. The increased IL-17 level positively correlates with neutrophil counts in the sputum of patients with moderate to severe asthma [79]. In addition, IL-17 levels in severe asthma patients’ serum are elevated compared to patients suffering from milder forms of asthma [80].

Th17 and Cancer: Modifications in oncogenes and tumor suppressor genes and/or epigenetic changes lead to tumor progression and local tissue invasion that cause the persistence of inflammatory cellular tumor infiltrates. The tumor causes the cellular infiltrates to sustain dysregulated inflammation, which immunologically is unresponsive to the tumor. The immune

ACCEPTED MANUSCRIPT 10 system can modulate the tumor microenvironment to limit tumor progression. Although the contributions of Th17 cells to autoimmunity and allergic response are well known their roles in

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cancer remain ambiguous, with evidence supporting tumor inhibitory as well as tumor promoting properties. For example in the B16 murine melanoma model adoptive transfer of in vitro

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polarized Th17 cells induced complete and lasting tumor regression. The Th17 cell-induced

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anti-tumor effect was IFN dependent as demonstrated by IFN neutralization [81]. In a mouse pancreatic tumor model, Pan02 cells transduced with the gene encoding IL-6 and injected into

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syngeneic mice led to an increase in tumor infiltrating Th17 cells and recruitment of IFN-

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producing CD8+T cells with delayed tumor growth and a better overall survival in comparison to controls [82]. Th17 cells have been demonstrated to have stem cell-like properties [83], hence the anti-tumor action of Th17 cells may be explained by their capacity to recruit cytotoxic by prolonged IFN- production by

Th1-like cells

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CD8+T lymphocytes effectors, probably

continuously trans differentiated from long-term self renewed stem-like Th17 cells. Despite

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studies in murine tumor models demonstrating that Th17 cells have an anti-tumor role, the Th17 cells that naturally infiltrate tumors appear to have a tumor-promoting effect. In multiple human malignancies including ovarian [84], hepatocellular [85], head and neck squamous cell [86], gastric [87], colorectal [88], breast [89] and pancreatic carcinomas [90], and melanoma [88], higher densities of Th17 cells are observed among tumor infiltrating T lymphocytes

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compared with homologous or adjacent non tumor tissues. This suggests that Th17 cells are recruited, induced, or expanded in the tumor microenvironment by tumor and tumor infiltrating host cell mediators. Tumor cells as well as tumor-derived fibroblasts secrete monocyte chemotactic protein 1 and RANTES that mediate the recruitment of Th17 cells [89]. In the peritumoral stroma of hepatocellular carcinoma, tumor-activated CD68+ monocytes and macrophages promote expansion of Th17 cells by secreting a set of proinflammatory cytokines including IL-1, IL-6, and IL-23 [91]. A high density of tumor infiltrating Th17 cells is found to

ACCEPTED MANUSCRIPT 11 have a bad prognosis for hepatocellular carcinoma [85], colorectal cancer [88], and pancreatic carcinoma [90]. In patients with hepatocellular carcinoma (HCC) the presence of IL-17-

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producing cells within tumors exhibits poor prognosis and high microvessel density [85]. Short survival rate and higher blood vessel density are also directly correlated with high levels of IL-17

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within the tumor in non-small-cell lung cancer patients [92]. No significant association was

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found between the density of IL-17A+ tumor infiltrating lymphocytes and survival of nasopharyngeal cancer patients [93]. Conversely, survival of ovarian carcinoma was better in

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patients with high Th17 density in tumor-associated ascites [94]. These contrasting results may

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rely on the different type of Th17 cells found in these different cancers. In ovarian tumors, Th17 cells co-express Th1 cytokines and could be considered proinflammatory with Th1 anti-tumor properties. Tumor-associated Th17 cells are inversely related to Tregs, while being positively

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correlated to levels of microenvironmental Th1 cells, cytotoxic CD8+T cells and natural killer cells [94, 95]. Nevertheless, Th17 cells were the main source of IL-17 in ascites in patients with

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ovarian cancer. In addition, the patients’ survival rate correlated positively with IL-17 levels within the patients’ fluids [96].

Similarly, data obtained from tumorigenesis studies with IL-17_/_ mice, devoid of Th17 cells, led to opposing conclusions on the anti tumor effects of IL-17. Whereas local and metastatic growth of MC38 colon carcinoma is enhanced, subcutaneous growth of B16 melanoma and MB49 bladder carcinoma is inhibited in IL-17-deficient mice in comparison to wild type hosts [97, 98]. As demonstrated, tumor infiltrating Th17 cells exhibit two opposite roles on tumor growth, either mediating an anti-tumor cytotoxic T cell response leading to tumor regression or promoting tumor growth by facilitating angiogenesis and suppressing immunity. Th17 and Sex Hormones: Sex hormones, especially estrogen, play an important role in Th17 cell development. For example, estrogen receptor alpha signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against EAE [99]. Similarly, progesterone promotes differentiation of human cord blood fetal T cells into T reg

ACCEPTED MANUSCRIPT 12 cells but suppresses differentiation into Th17 cells and expression of cytokines IL-17-A, IL-17F, and IL-21[100].

We have found that estrogen treatment of human peripheral blood

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mononuclear cells (PBMCs) leads to an increase in the production of IL-6, IL-12, IL-17 and IL21 cytokines and CD3+IFN- and CD3+CD69+T cells (unpublished). These studies indicate that

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sex hormones, especially estrogen, play a significant role in the development and function of

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Th17 cells. However, further studies are required to delineate the mechanistic role of sex hormones in Th17 pathobiology.

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Mesenchymal Stem Cells and Th17

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Mesenchymal stem cells (MSCs) have been identified as immunomodulating cells as they inhibit the generation and function of Th1 cells, inhibit Th2 through Treg induction, increase Treg cell formation and IL-10 secreting properties of Treg cells, and reduce the formation, proliferation,

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and target cell lysis of cytotoxic lymphocytes. Additionally, MSCs are able to inhibit B cell proliferation and dendritic cell function [101, 102]. Specifically with respect to Th17 cells, human

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MSCs (hMSCs) have been shown to inhibit the differentiation of Th17 cells from naïve CD4+ T cells and inhibited production of the Th17 cytokines IL-17, IL-22, IFN-γ, and TNFα [103]. Under inflammatory conditions, cell contact of MSCs with CD4+ T cells was shown to occur via CCL20, interacting with the CC receptor 6 that appeared to be mediated by PGE2 that initiated the regulatory function of hMSCs on Th17 cells. Furthermore, this interaction was associated with increased hMSC production of IL-10, and epigenetic regulation to suppress the RORC gene associated with Th17 generation and to enhance expression of FOXP3 associated with the induction of Treg cells. Others have shown that the suppression of Th17 cell production of IL17A and IFN-γ by hMSCs is dependent on the expression of CD39 and CD73, which suggests that adenosine may play a role in the immunomodulatory effect [104].

Using mouse MSCs (mMSCs), similar observations of Th17 inhibition by mMSCs have been reported. IL-10 secretion by mMSCs appears to be a key soluble mediator in Th17 inhibition

ACCEPTED MANUSCRIPT 13 through the suppression of mouse RORγt, the transcription factor necessary for Th17 generation, via the activation suppressor of cytokine signaling 3 (SOCS3) and suppression of

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signal transducers and activators of transcription 3 (STAT3) [105, 106]. However unlike with hMSCs, mMSC contact with naïve T-cells is not necessary for the immunosuppressive effect

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[105, 106], although others have reported that cell-cell contact was essential in the mMSC

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immunosuppressive effect on Th17 cells [101]. However it appears that the requirement for cellcell contact may be dependent on mouse species of origin of mMSCs or the ratio of mMSCs to

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T-cells as higher mMSC/T-cell ratios resulted in suppression of Th17 cells in the absence of

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cell-cell contact [101]. Thus the ability of Th17 cells to secrete IL-17 is also dependent on the ratio of mMSC to T cells, where IL-17 expression from mature Th17 cells is inhibited only at higher ratios but not at lower ratios [105]. Similar to hMSCs suppression of Th17 cells, PGE2

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binding to the EP4 prostaglandin receptor appears to also be important in suppressing the induction of Th17 cells in the mouse system [107]. Also cell-cell contact induction of

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programmed death 1 (PD-1) and ligand for PD-1 (PD-L1) have also been suggested to mediate suppression of mature Th17 cells [105]. Thus MSCs may have varying immunosuppressive effects depending on stage of Th17 differentiation. Finally, it has been observed that mMSCs may not only suppress Th17 cells but can also enhance or stimulate their generation [108]. The stimulatory or proinflammatory effect of mMSCs on Th 17 cells appears to be dependent on the timing of when mMSCs are exposed to CD4+ cells and the state of activation of CD4+ cells [108]. Thus mMSC exposure to already activated CD4+ cells yields IL-17 secreting Th17 cells while exposure of mMSCs to naïve unactivated CD4+ cells results in suppression of Th17 cell generation. Determinants of whether mMSCs can exert anti-inflammatory and Th17 suppressive effects versus pro-inflammatory up-regulation of Th17 cells may also be dependent on the balance between IL-6 and TGF-β. While quiescent mMSCs secrete TGF-β which can regulate the development of naïve T-cells into anti-inflammatory Treg cells, the inflammatory milieu with the presence of pro-inflammatory cytokines (IL-1 and TNFα), mMSCs secrete IL-6 and together

ACCEPTED MANUSCRIPT 14 with TGF-β, stimulate the expression of RORγt leading to the generation of pro-inflammatory Th17 cells [109]. The spontaneous production of TGF-β but not IL-6 is also seen in unstimulated

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hMSCs, but IL-6 production by hMSCs is stimulated by co-culture with peripheral blood mononuclear cells, and thus it would appear that the balance between TGF-β and IL-6 to either

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be immunosuppressive and anti-inflammatory with the generation of Treg cells or pro-

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inflammatory with the generation of Th17 cells would probably hold true in the human situation.

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The use of immunomodulatory MSCs as potential therapy for autoimmune and inflammatory diseases has recently been explored. In mouse models of CIA, Th17 cell induction was inhibited

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by mMSCs transduced to express TGF-β while Treg cells were enhanced resulting in the prevention of CID [110]. Human adipose-derived MSCs (hADMSCs) were also able to inhibit

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Th17 generation, stimulate the production of IL-10, and induce Treg cell formation [111, 112].

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Human umbilical cord MSCs were also reported to decrease the secretion of IL-17, TNFα, and

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IL-6 when mixed with peripheral blood mononuclear cells from patients with rheumatoid arthritis but not from healthy controls. Additionally, RORγ was also reduced suggesting that Th17 cell formation was also impaired [113].

Human bone marrow-derived MSCs have also been

reported to suppress Th17 cells in murine EAE models [114, 115] . However there have been other reports that at least with bone-marrow derived hMSCs co-cultured with peripheral blood mononuclear cells from rheumatoid arthritis patients, Th17 cell expansion occurred and IL-17A mRNA and protein were enhanced [116]. Similarly it was reported when human peripheral blood mononuclear cells from healthy donors were treated with anti-CD3, anti-CD-28, IL-23, anti-IL-4, and anti-IFN-γ antibodies for 3 days and exposed to MSC conditioned medium, while Th1 proliferation was inhibited, Th17 proliferation and IL-17A production were increased while IL-10 secretion was decreased [117].

Thus the use of hMSCs in autoimmune or inflammatory

diseases needs to be further explored, as factors such as degree or length of disease activity, cytokine profile or other pathogen-associated molecules in the microenvironment of diseased

ACCEPTED MANUSCRIPT 15 tissue could potentially affect the immunosuppressive or immunostimulatory contribution of hMSCs.

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Conclusions: Recent advances in Th17 cell research have substantially broadened our understanding of the pathogenesis of certain immunological diseases. In this article we briefly

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reviewed current information on the different functions and roles of Th17 cells in autoimmunity

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and inflammation. Th17 cells predominantly produce IL-17 (IL-17A), IL-17F, and IL-22, thus inducing immense tissue reactions due to the wide distribution of IL-17 and IL-22 receptors. To

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communicate with other immune cells, Th17 cells also secrete IL-21. Dysregulation of Th17-

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related cytokines, IL-17 and IL-22, has been implicated in psoriasis, RA, MS, T1D, Crohn’s, and other diseases. Both cytokines are pro-inflammatory and therefore important players in the pathogenesis of various autoimmune and inflammatory disorders. Studies on IL-17, IL-17R, IL-

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22, IL-22R, and/or their signaling pathways in disease states could provide potential therapeutic

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drug targets for evaluation in clinical trials for inflammatory and autoimmune disease.

ACCEPTED MANUSCRIPT 16 Figure Legend:

Cyotkine / Chemokine

Type of Action

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Related Disorder

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Figure 1 indicates role of Th17 cells in various diseases and their mode of action.

Ref.

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Differentiation

CD4+ Th17 cells

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Naïve CD4+ T cells

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ROR RORt STAT3 IRF4 AhR, c-Maf NOTCH BATF Runx1

IL-1β, TNF, IL-6, TGFβ, IL-12, IL-15, IL-21, IL-22, IL-23, CCR6, CD161, estrogen, sodium

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Transcription Factors

Cytokines and Chemokines

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Inhibition

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IL-2, IL-4, IL-25, IL-27, SOCS1, SOCS3, Vitamin D, Retinoic Acid

IL-17A, IL-17F, IL-21, IL-22, TNF-, IL-9, IL-10, IFN-, CCL-20, RANKL G-CSF. GMCSF

Inflammation Bone erosion Cartilage destruction Autoimmunity Chemotaxis Thrombosis

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Figure 2.The proposed model of Th17 cells development. The differentiation of Th17 is controlled by the key transcription factor

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RORt. Th17 cell development occurs in the presence of IL-6, TGFβ, IL-21, IL-22, IL-23, IL-1β, TNF-, sodium and estrogen (E2), while abrogation of Th17 cell differentiation is mediated by the presence of IL-2, IL-4, IL-25, IL-27, SOCS1, SOCS3, Vitamin D and Retinoic acid. Ultimately, Th17 cell expression can lead to inflammation, autoimmunity, bone erosion, chemotaxis, thrombosis and cartilage destruction.

ACCEPTED MANUSCRIPT 18 References Cited;

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