HHS Public Access Author manuscript Author Manuscript

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: Inflamm Bowel Dis. 2016 June ; 22(6): 1473–1482. doi:10.1097/MIB.0000000000000775.

Microbiota-specific Th17 cells: Yin and Yang in regulation of inflammatory bowel disease Wu Wei, MD1,2,*, Chen Feidi, MD3,*, Liu Zhanju, MD, PhD2, and Cong Yingzi, PhD1,3 1Department

of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX

2Department

Author Manuscript

of Gastroenterology, The Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China

3Department

of Pathology, University of Texas Medical Branch, Galveston, TX

Abstract

Author Manuscript

Multiple mechanisms are involved in regulation of host response to microbiota to maintain the intestinal homeostasis. Th17 cells are enriched in the intestinal lamina propria (LP) under steady conditions. Many studies have demonstrated that microbiota reactive Th17 cells in the intestines mediate the pathogenesis of inflammatory bowel diseases. However, clinical trials of anti-IL-17A or anti-IL-17RA antibodies in patients with Crohn’s Disease show no improvement or even exacerbation of disease. Accumulating data has also indicated that Th17 cells may provide a protective effect as well to the intestines from inflammatory insults under homeostasis regulation, even under inflammatory conditions. Thus both pro-inflammatory and anti-inflammatory functions of intestinal Th17 cells have emerged under various conditions. In this review article, we will summarize recent progresses of Th17 cells in regulation of intestinal homeostasis as well as in the pathogenesis of inflammatory bowel diseases.

Keywords Microbiota; Th17; IBD

Introduction

Author Manuscript

The mammalian gastrointestinal tract of harbors an extraordinary huge number of diverse microorganisms, comprising 1013–14 bacteria with more than 1000 strains, termed the commensal microbiota.1, 2 The commensal microbiota not only participates in the breakdown of food and energy metabolism, but also contributes to the regulation of host immune response and homeostasis. Multiple mechanisms involving both innate and adoptive immune responses have been developed in regulation of host response to microbiota to maintain the homeostasis. These regulatory mechanisms play a crucial role in restraining the

Corresponding author: Yingzi Cong, Ph.D. Department of Microbiology and Immunology, University of Texas Medical Branch, 4.142C Medical Research Building, 301 University Blvd, Galveston, TX 77555-1019. Phone: (409) 772-4902. Fax: (409) 772-5065. [email protected]. *WW and FC contribute equally. The authors have no conflicts of interest to disclose.

Wei et al.

Page 2

Author Manuscript Author Manuscript Author Manuscript

adoptive immune system. While several innate immune pathways have been identified to be important in the regulation of intestinal homeostasis, deficiencies in these pathways require an intact adoptive immune system in order to elicit intestinal inflammation, whereas the absence of adoptive immune components limits inflammation. Elegant works by Fiona Powrie and her colleagues decades ago demonstrated a central role of CD4+ T cells in mediating colitis, in that adoptive transfer of CD4+CD45RBhi T cells induced colitis development in immune deficient RAG−/− mice, which do not have T cells and B cells, under specific pathogen-free (SPF) conditions.3 However, the recipient mice did not develop colitis with a reduced bacterial load or raised under GF conditions4, indicating that intestinal inflammation is driven by resident bacteria. The importance of microbiota antigen-specific T cells in mediating development of colitis was demonstrated subsequently, in that CD4+ T cells were highly reactive to microbiota antigens in C3H/HejBir mice, a spontaneous model of experimental colitis. CD4+ T cells isolated from the colitic mice were able to transfer colitis in severe combined immunodeficient (SCID) mice when activated by microbiota antigens.5 Among different subsets of CD4+ T cells, Th17 cells are enriched in the intestinal lamina propria (LP).6 Prevailing evidence has demonstrated that microbiota reactive Th17 cells in the intestines mediate the pathogenesis of inflammatory bowel diseases. However, clinical trials of anti-IL-17A or anti-IL-17RA antibodies in patients with Crohn’s Disease (CD) showed either no improvement or even exacerbation of symptoms.7, 8 Although disappointing clinically, these findings are consistent with the emerging data showing that Th17 cells may also provide a protective effect to the intestines from inflammatory insults under homeostasis regulation, even under inflammatory conditions. Thus both proinflammatory and anti-inflammatory roles of intestinal Th17 cells have been emerged under various conditions. In this review article, we will summarize recent progresses of Th17 cells in regulation of intestinal homeostasis and the pathogenesis of inflammatory bowel diseases (IBD), and provide some personal thoughts regarding the “Yin” and “Yang” of Th17 cells in IBD as well as potential therapeutic targets in Th17 pathways in treatment of IBD.

The role of CD4+ T cells in inflammatory bowel disease CD4+ T cell lineages

Author Manuscript

Based on expression of T cell receptors (TCR), T cells can be divided into αβT cells and γδT cells. αβT cells are primarily responsible for antigen-specific cellular immunity, while γδT cells are non-MHC-restricted and mostly involved in primary immune responses.9 In peripheral, the vast majority of T cells are αβT cells, and only a minor portion (1–5%) are γδT cells.10 In intestines, however, γδT cells constitute a large portion of intraepithelial lymphocytes (IELs), which regulate the continuous turnover of intestinal epithelial cells as well as the maintenance of epithelial barrier function by restricting pathogen transmigration, whereas majority of T cells in LP are αβT cells.10 Naive CD4+ T cells can differentiate into different lineages upon activation by antigens presented by antigen-presenting cells (APCs) under different cytokine cues. The prevailing dogma for many years was that CD4+ T cells fell into two lineages: interleukin-12 (IL-12) induces naïve CD4+ T cells differentiate into Th1 cells, which produce dominantly interferon-γ (IFNγ), while IL-4 induces differentiation of Th2 cells, which produce IL-4 and IL-5.11, 12 More recently, Th17 cells joined the field as a distinct T cell lineage, which produce signature cytokine IL-17 (also known as IL-17A) under the induction of TGFβ, IL-6 or other cytokines.13, 14 This paradigm shift was due to a

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 3

Author Manuscript

key finding that IL-23, a heterodimer which shares its p40 subunit with IL-12 in addition to its p19 subunit, was required for Th17 cell activity in vivo (Figure 1).15, 16 All of these T cell subsets are present in the intestinal LP.

Microbiota antigen-specific CD4+ T cells in IBD

Author Manuscript

Given their central role in regulating both innate and adaptive immunity, CD4+ T cells are key to both protection and pathogenesis of chronic inflammation. Inappropriate or dysregulated CD4+ T cell responses have been characterized in many chronic inflammatory diseases. The importance of CD4+ T cells in the development of IBD has been demonstrated in different models of experimental colitis as well as numerous clinical observations. Elegant studies by Fiona Powrie and her colleagues decades ago demonstrated that reconstitution of SCID mice with CD4+ T cells induced colitis.3 In this well studied model, transfer of naïve CD4+CD45RBhi T cells into SCID or RAG−/− recipient mice resulted in severe colitis in 4–6 weeks based on the genetic background of the recipient mice.3, 17 Importantly, while the recipient mice developed colonic inflammation when housed in SPF environment, no colitis evolved in the recipient mice under GF conditions. This colitis model, thus, clearly demonstrates the vital role of CD4+ T cells in response to gut microbiota in chronic intestinal inflammation.

Author Manuscript

The crucial role of microbiota antigen-specific CD4+ T cells in mediating development of colitis was further confirmed in a series of sequential studies using a spontaneous colitis model. As a substrain of C3H/HeJ mice, C3H/HeJBir is highly susceptible to development of colitis. Under certain housing conditions, they can develop colitis spontaneously.18 The colitis, which is focal, mainly localized in the cecum, develops at age of 4–6 weeks, and resolves by 3 months of age. Those mice demonstrated high levels of B-cell and T-cell responses to microbiota antigens.5, 19 When transferred into histocompatible SCID mice, C3H/HeJBir CD4+ T cells reactive to cecal bacterial antigens (CBA) induced colitis in the recipients.5 This finding thus provided the first formal evidence that effector CD4+ T cells reactive to enteric bacterial antigens can cause experimental colitis. In following up studies, CBir1 flagellin, an immunodominant microbiota antigen was identified in multiple animal models of colitis as well as in patients with Crohn’s disease.20, 21 Importantly, transfer of CBir1-specific CD4+ T cells was able to induce colitis in immune compromised mice.20, 21 Taken together, those studies demonstrated that CD4+ T cells reactive to a single microbiota antigen can cause colitis, which is consistent with the hypothesis that a limited set of immunodominant antigens in the microbiota can activate pathogenic effector T cells and induce colitis. Some of such antigens may be specific to one strain or model, but others such as flagellins appear to cross both strains and species.22

Author Manuscript

Consistent with the findings from animal studies, the increased and dysregulated CD4+ T cell response to microbiota antigens was also observed in IBD patients.23 The expression of mucosal cytokines which potentially regulate development of different subsets of CD4+ T cells has also demonstrated in patients with IBD. Crohn’s disease is characterized for its Th1 cytokine pattern, late for its Th17 cytokine pattern, whereas ulcerative colitis has demonstrated a unique Th2 profile.24 Aberrant T cells and inflammatory cytokines were thereby the focus of studies designed to develop a therapeutic strategy to treat the patients

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 4

Author Manuscript

with IBD in recent years. For example, in a subsequent multicenter clinical trial, a monoclonal antibody against IL-12p40 showed a great promise in treating patients with Crohn’s disease.25 As mentioned earlier, IL-12p40 is a subunit shared by IL-12 and IL-23, two key cytokines important in driving Th1 and Th17 cell development, respectively, the efficacious effects with anti-IL-12p40 antibody thus highlight the crucial role of Th1 and Th17 cells in the pathogenesis of IBD.

Th17 development in intestines

Author Manuscript

Th17 cells are prominent population among the T cells present in the normal intestinal lamina propria. Th17 cells produce their signature cytokines IL-17A (IL-17), IL-17F, IL-21, and IL-22. IL-17A and IL-17F stimulate innate immune cells and epithelial cells to produce IL-1, IL-6, and G-MSF and IL-8 (CXCL8), which induce increased neutrophil production and recruitment and provide proinflammatory signals.14, 26, 27 IL-22, a member of the IL-10 cytokine family, stimulates epithelial cells of barrier tissues to enhance antimicrobial defense and epithelial barrier integrity.28, 29

Author Manuscript

Unique differentiation factors and transcription factors distinguish the Th17 lineage from other CD4+ T cell subsets. Similar to other subsets of CD4+ T cells, the initiation of Th17 lineage is dictated by a special cytokine cue. Soon after the identification of Th17 cells, transforming growth factor β (TGFβ) and IL-6 were reported to differentiate naïve T cells to Th17 cells.30 Retinoic acid-related orphan receptor γt (RORγt) and RORα appearred to be key transcription factors involved in Th17 cell differentiation.6 Later on, intense efforts reveal that IL-1β, and IL-21 also contributed to Th17 cell development.31 Altogether, combinations of cytokines and TCR signaling enable activation of STAT3 in naïve T cells, which promote the expression of lineage specific transcriptional regulator RORγt, eventually leading to Th17 phenotype.32 It is clear now that Th17 cell differentiation involves several stages. After differentiation phase initiated by antigen stimulation, Th17 cells produce a large amount of IL-21, which in turn to further promote expansion and differentiation of Th17 cells. This stage is thus called “Th17 cell amplification”. IL-21 promotes IL-23 receptor expression in differentiated Th17 cells. Although IL-23R is not expressed on naïve T cells, IL-23 has been shown to serve as an important factor in maintenance to preserve RORgt function and stabilization and surviving of Th17 cells.33, 34 In particular, IL-6 together with IL-23 are able to induce Th17 cells in the absent of TGFβ.35 However, the gene profiles of Th17 cells under different polarized conditions have significant differences, indicating that they may function differently.36 It has been proposed that Th17 cells generated from TGFβ and IL-6 are non-pathogenic, and important for immune homeostasis, whereas IL-23 and IL-6 induce pathogenic Th17 cells.

Author Manuscript

Th17 cells are not found in intestines of mice housed under GF conditions, indicating that microbiota is responsible for the generation of this subset.37 Segmented filamentous bacteria (SFB), an organism that inhabits the ileum in low abundance, has been identified as a potent inducer of Th17 cells in the intestines.37 RORγt+ Th17 cells were induced in the tissuedraining lymph nodes early after SFB colonization and distributed throughout the length of the gut. However, the production of IL-17A was restricted to the ileum, in which SFB makes direct contact with the epithelium and induces serum amyloid A proteins 1 and 2

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 5

Author Manuscript

(SAA1/2).38 SFB not only initiated gut Th17 responses in and outside gut organized lymphoid tissue, but also induced intestinal IgA responses. Thus, SFB could stimulate multiple pathways in intestinal inductive sites, which cooperate to generate some specific but mainly non-specific gut homeostatic IgA and Th17 cell responses.39 Other commensal bacteria can also stimulate intestinal Th17 cells, including altered Schaedler flora which contain eight known bacteria.40

Author Manuscript

How the microbiota stimulates intestinal Th17 cell development is still not completely understood. Recent reports indicated that the bacterial context of cognate antigen delivery dictates the fate of the antigen-specific T cells. SFB primed and induced Th17 cells locally in the LP in an MHCII-dependent manner. In SFB-colonized mice, most Th17 cells, but not other T cells, recognized SFB antigens. Further, T cells with antigen receptors specific for SFB antigens developed into Th17 cells.41, 42 In addition to potential role of antigen stimulation by microbiota, specific Toll-like receptor (TLR)-TLR ligand interactions have been implicated in driving intestinal Th17 cell development. A subset of CD11chiCD11bhi lamina propria dendritic cells (LPDCs) that express TLR5 in the small intestine were able to stimulate naïve T cells differentiate into Th17 cells. Interestingly, such TLR5-expressing LPDCs also promoted intestinal IgA production.43 CD172α+ LPDCs have also been shown to induce Th17 cell development.44

Author Manuscript

The microRNAs (miR), a class of non-coding, small RNAs, have been shown to play a vital role in the immune homeostasis. Several miRs have been identified in regulation of Th17 cell development.45, 46 MiR-21 was able to promote Th17 cell development by targeting and inhibiting SMAD-7, which negatively regulates TGF-β signaling.45 MiR-301a promoted Th17 cell differentiation by targeting the IL-6/23–STAT3 pathway.46 MiR-10a, which is mainly expressed in intestines, can be downregulated by microbiota via TLR-TLR ligand interactions through a MyD88-dependent pathway. IL-12/IL-23p40, which is a crucial molecule in driving Th1 and Th17 cell development, was identified as a target of miR-10a,47 suggesting that microbiota downregulation of miR-10a could potentially promote Th17 cells in the intestines. In the inflamed mucosa of patients with IBD, Th17 cells were increased while miR-10a expression is decreased. Sequential studies further indicated that miR-10a downregulated mucosal inflammatory response through inhibition of IL-12/IL-23p40 and NOD2 expression, and blockade of Th17 cell immune responses.48 MiR-29, which can be induced by the intracellular sensor NOD2, limited IL-23 release to decrease IL-17 production and eliminate Th17-associated intestinal inflammation.

Th17 cells in pathogenesis of IBD Author Manuscript

Based on genome-wide association studies (GWAS), various polymorphisms in genes encoding components of the Th17 cell pathway, such as IL23R and STAT3, are associated with IBD (Table 1). Increased amounts of both IL-23 and IL-17 were detected in IBD in humans as well as in multiple models of experimental colitis.49–52 Accumulating evidence indicates that Th17 cells are involved in the priming and differentiation of pro-inflammatory cytokines in the pathogenesis of IBD. Upon microbiota antigen stimulation, Th17 cells produce several pro-inflammatory effector molecules which mediate inflammatory cell infiltration and tissue destruction, including pro-inflammatory cytokines, chemokines, and

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 6

Author Manuscript

matrix metalloproteases. In addition, Th17 cells also produce various cytokines, which in turn stimulate production of other pro-inflammatory mediators by intestinal endothelial cells, myofibroblasts, and epithelial cells.

Th17 Cells in experimental colitis

Author Manuscript Author Manuscript

The first formal demonstration of Th17 cells playing an important role in IBD comes from the finding that IL-23, but not IL-12, was required for the spontaneous development of colitis in IL-10−/− mice.53 In this study, IL-23 targeted a unique subset of tissue-homing memory T cells in IL-10−/− mice, which were activated by IL-23 to produce the proinflammatory cytokines IL-17 and IL-6.53 In the CD45RBhi transfer colitis model, both IL-17-producing Th17 cells and IFNγ-producing Th1 cells were present in the inflamed intestinal tissues of the colitic recipient mice. Transfer of RORγt-deficient CD45RBhi T cells, which fail to develop into Th17 cells, did not induce colitis in the recipients, indicating a role of Th17 cells.54 IL-23 signaling plays a crucial role in this model. Transfer of CD4+CD45RBhi T cells that lack IL-23R, thus do not respond to IL-23 stimulation, did not induce colitis in Rag−/− mice.55 Furthermore, transfer of CD4+CD45RBhi T cells into IL-23p19−/−Rag−/− mice, which do not produce IL-23, also failed to induce colitis.56 Consistently, in the microbiota antigen-specific T cell transfer model as mentioned earlier, Th17 cells were predominant over Th1 cells in the lamina propria of the inflamed colon in SCID recipient mice at a 5:1 ration. Small numbers of Th17 cells reactive to microbiota antigens were able to transfer colitis in SCID mice. In addition, neutralization of IL-23 by injection of anti-IL-23p19 monoclonal antibody not only prevented colitis but also abrogated already established colitis, suggesting that Th17 cells reactive to microbiota antigens mediate inflammation in this colitis model.33 In following up studies, transfer of Th17 from T cell receptor transgenic (CBir1 Tg) mice, which are specific for CBir1 flagellin, a dominant microbiota antigens present in multiple models of colitis and the patients with Crohn’s disease, induced severe colitis in RAG−/− mice, whereas transfer of CBir1 specific Th1 cells only induced a mild colitis,49 indicating microbiota antigen-specific Th17 cells are dominant in induction of experimental colitis.

Author Manuscript

Although a pathogenic role for the Th17 pathway has been established in models of colitis, Th17 cells are not stable, and can convert into IFNγ-producing Th1 cells and other effector T cells under the condition of intestinal inflammation.49, 57 Th17 cells from CBir1 Tg mice induced severe colitis when transferred into TCRβδ−/− mice, which lack T cells. High levels of IL-12, IL-23, and as well as the numbers of IFNγ+ Th1 cells were present in the inflamed colons of Th17 cell recipients. Meanwhile, anti-IL-17 mAb abrogated Th17-induced colitis to some extent, reduced colonic IL-12 and IL-23 production and eliminated IFNγ+ Th1 cell induction. These data indicated that Th17 cell conversion to Th1 cell could provide the pathogenic effect of both cell types to induce intestinal inflammation.49 IL-17 produced by Th17 cells stimulated IL-12 and IL-23 production in colonic dendritic cells, which promoted conversion of Th17 cells into Th1 cells.49 Large amount of T cells which produce both IL-17 and IFNγ gradually accumulate in the inflamed intestinal tissues with the progression of colitis development in various animal models of colitis, including CD4+CD45RBhi T cell transfer model and CBir1 T cell transfer

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 7

Author Manuscript

model,49, 57 which have been speculated to be the “pathogenic” T cells for experimental colitis and human IBD. Indeed, an elegant study demonstrated recently that when transferred into RAG−/− mice, IFNγ-deficient Th17 cells retained an IL-17A+ phenotype, and did not induce colitis in recipients.58 Development of colitis required the conversion of Th17 cells into IFNγ-producing Th1 cells and was contingent on both Stat4 and T-bet expression. Consistently, it has been shown that a qualitative shift of the Th17 population toward IFNγ+ IL-17+ coproducing CD4+ T cells at active inflammatory mucosal sites in IBD patients.59

Th17 cells in human IBD

Author Manuscript

Human IBD is consistent of two major forms: Crohn’s disease (CD) and ulcerative colitis (UC). CD is characterized by chronic and relapsing inflammation of intestinal segments, which primarily involves the small and large intestine, but can also affect other parts of the GI track as well. The exact mechanism(s) involved in the pathogenesis of CD is still not completely clear. The importance of Th17 cells in CD was implicated in data from GWAS. A single nucleotide polymorphism in the IL-23R gene was found to be associated with decreased susceptibility to CD,60 thus links IL-23R and IBD.60 Multiple CD-linked genetic susceptibility variants of IL23R have been identified now, as well as other genes of the Th17 pathway, including STAT3, RORc, IRF8, IL12b, ICOSLG and TNFSF15 (Table 1),60, 61 which supports the notion that IL-23-driven Th17 cells are mostly pathogenic in the development of CD . Th17 cells were increased in CD lesions.62 Increased expression of IL-17 and IL-23 has been found in CD lesions.50, 51 Other Th17 cytokines, IL-22 was also increased in the active lesions of CD, and increased serum levels of IL-22 has been shown to correlate with disease activity.63 Further, IL-2/IL-21 region has also been associated with CD.

Author Manuscript

Myeloid DCs isolated from mesenteric lymph nodes (MLN) of CD patients produced a higher amount of IL-23 and a lower amount of IL-10, and induced stronger Th17/Th1 immune responses, which could be responsible for the pathogenesis of CD.52 Recent data indicated that IL-23 can support both Th17 and Th1 responses in humans.64 Monoclonal antibodies to the common subunit of IL-23 and IL-12, IL-12/IL-23p40 as well as IL-23p19, have shown efficacy in treatment of CD in recent clinical trials. However, clinical trials of anti-IL-17A or anti-IL-17RA antibodies in CD showed no improvement or even exacerbation of disease.7, 8 The reasons for this failure are still unclear and warranty further investigations.

Author Manuscript

UC primarily involves colon, with contiguous extension of disease proximally from the rectum. Although Th2 cytokines have been proposed to be involved in the pathogenesis of UC, the exact pathogenic mechanisms are not completely understood. Increased production of IL-5 and IL-13 but not IL-4 has been found in LP CD4+ T cells isolated from inflamed colons of UC patients.65 In a later study, it has been shown that the presence of NKT cells in the LP of UC lead to ulceration and inflammation by NKT-cell-mediated cytotoxicity. Interestingly, IL-13 enhanced such tissue injures, which augmented NKT cell cytotoxicity and had effects on epithelial cell integrity.66 IL-17 and IL-22 were also found, in several recent studies, to be increased in UC patients compared to healthy controls, although to a lesser degree than in CD lesions.50, 52 GWAS have linked IL23R and Th17 pathway and

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 8

Author Manuscript

related immune mediated genes to UC. Some of them are also linked to CD, including IL-23R, RORc, AHR, IL-2/IL-21, STAT3, ICOSLG and TNFSF15 (Table 1).60, 61 However, it is still unclear at the current time whether and how Th17- and NKT/IL-13-responses act in cooperation to mediate the pathogenesis of UC, whether these two pathways occur in varying proportions in UC or that disease in different UC patients has a distinct pathogenic cause.

Th17 cells in protection of IBD

Author Manuscript

Although prevailing data implicate Th17 cells in the pathogenesis of IBD both in experimental colitis and human IBD, the failure in clinical trials of anti-IL-17A or antiIL-17RA antibodies in CD,7, 8 indicates that the role of Th17 cells in IBD is more complicated than we originally thought. Enrichment of Th17 cells in intestines in both human and mouse indicates they may actually contribute to the maintenance of intestinal homeostasis. It is becoming clear that Th17 cells are indispensable in intestinal homeostasis as evidenced by the increased intestinal bacteria load found in IL-23p19−/− and IL-23R−/− mice in the absence of Th17 cells.67

IL-17 in preservation of intestinal epithelial barrier

Author Manuscript Author Manuscript

IL-17 is the signature cytokine of Th17 cells. Accumulating evidence suggests a protective role for IL-17 (Figure 2). IL-17-mediated protection was reported in CD4+CD45RBhi T cell transfer model.68 Adoptive transfer of CD45RBhi T cells deficient in IL-17 resulted in worsen colitis in RAG−/− recipient mice compared to wild type controls which was correlated with higher expression of genes encoding Th1-type cytokines in colon tissues. Furthermore, T cells deficient in the IL-17 receptor resulted in an accelerated, aggressive colitis in recipient mice. In IBD, inflammatory cytokines drive destruction of epithelial cells, in part due to breakdown of intercellular tight junctions. IL-17 was recently demonstrated to stimulate intestinal epithelial cell proliferation and healing through a cooperative signaling pathway with the fibroblast growth factor receptor (FGFR).69 Consistently, IL-17 in colitis was able to preserve the intestinal epithelial barrier, despite the potential of IL-17 to drive pathogenic inflammation. In response to DSS insult, IL-17−/− mice developed more severe colitis compared to WT mice. Intestine permeability in IL-17−/− mice was increased, which was associated with abnormal subcellular localization of the tight junction protein occluding.70 In Helicobacter bilis-infected Abcb1a−/− mice which develop colitis, IL-17A was suggested as the major effector cytokine among IL-17 subtypes.71 The absence of Th17 cells depleted the majority of IL-17 in the intestine which resulted in subsequent functional deficiency in epithelial protection (Figure 2). Consistent with this, increased bacterial translocation has been detected in the mesenteric lymph nodes of IL-17R−/− mice which suffered more severe DSS-induced chronic colitis compared to wide type counterparts. Similar results have been obtained in the acute colitis model that DSS recipient mice with anti-IL-17A treatment presented exacerbated colitis.72 IL-17-induced antimicrobial peptides from epithelial cells remain a crucial component in host defense against commensal bacteria.73, 74 IL-17 has been demonstrated to induce production of β-defensin 2 (hBD-2), hBD-3, S100A7, S100A8, and S100A9. IL-17F, on the

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 9

Author Manuscript

other hand, potently promote the transcription of hBD-2, S100A8 and S100A9.75, 76 Besides antimicrobial peptide secretion, Th17 cell-derived IL-17 and IL-17F can also enhance neutrophil recruitment by stimulating expression of various CXC chemokines, cytokines and growth factors.26, 77

Th17-IgA axis in protection of intestinal inflammation

Author Manuscript Author Manuscript

Th17 cells are potent inducers of B cell class switching. Immunoglobulin A (IgA) represents the most abundant antibody isotype in intestines, which segregates the microbiota from attaching to the intestinal epithelium, and limiting contact with the intestinal immune cells. Compromise in IgA-mediated protection can result in unwanted activation of resident immune cells and aberrant chronic inflammatory state in the intestine that defines IBD. Indeed, increased prevalence of mucosal infections and inflammation has been found in patients with either selective IgA deficiency (SIgAD) or common variable immunodeficiency (CVID).78 Emerging evidence suggests that Th17 cells promote intestinal IgA production. Mice in the absence of either CD4+ T cells (TCRβxδ−/− mice) or IL-17 signaling (IL-17R−/−) present significantly impaired level of IgA, suggesting a predominant role of Th17 cells in the T cell-dependent IgA production.72 After production by plasma cells, IgA undergoes transepithelial transportation chaperoned by the polymeric Ig receptor (pIgR), a rate-limiting protein expressed on the basolateral surface of epithelial cells. PIgR is also partially secreted with IgA to improve stability of secretory IgA (sIgA). Repletion of TCRβxδ−/− mice with microbiota-specific Th17 cells induce increased pIgR expression in the intestine as well as elevating fecal IgA levels. The finding that blockade of IL-17A abolishes the enhancement of IgA secretion after replenishment of Th17 cells, and that IL-17R−/− mice have decreased pIgR level compared to wide type, signify the role of IL-17 in IgA secretion via regulating pIgR.72 Consistently, H. bilis-infected Abcb1a−/− mice receiving anti-IL-17RA treatment display decreased Pigr expression.71 Further exploration of the mechanisms revealed that IL-17 directly induces pIgR expression on epithelial cells in a NF-κB and PI3K-dependent manner.72 Follicular helper T (Tfh) cells interact with B cells and facilitate somatic hypermutation as well as IgA class switching. Importantly, intestinal Th17 cells can also convert into Tfh cells in Peyer’s patches as a way to induce intestinal IgA production.79

Author Manuscript

Th17 cells can directly promote B cell IgA production as well, which is mediated mainly by IL-21, but not IL-17.80 In fact, IL-21−/− and IL-21R−/− mice with deficient IL- 21 signaling present decreased IgA level compared to wide type mice.80 IL-21 not only augments IL-4driven IgG production, but also positively regulates transforming growth factor β (TGFβ)mediated IgA production by enhancing IgA class switch recombination (CSR) (Figure 2).80, 81 IL-21 also contributes to B cell mucosal homing by inducing α4β7. Moreover, IL-21 and IL-17 work synergistically to induce the generation of germinal centers (GCs) as transfer of Th17 cells into IL-17R−/− or IL-21R−/− mice fail to rescue the size and number of GCs in the draining lymph nodes and spleen.80 Exogenous IL-21 also positively regulates IL-22 production in CD4+ T cells. IL-21R−/− mice receiving DSS developed more severe colitis compared to control mice.82

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 10

Author Manuscript

IL-22 promotion of intestinal tissue repair

Author Manuscript

IL-22 has been correlated with IBD with altered expression of IL-22 found in colon biopsy samples from IBD patients and experimental colitis.83, 84 To date, various animal models of colitis have suggested a protective role for Th17-IL-22 axis. In DSS-induced acute colitis model, IL-22−/− mice presented worsen inflammation than wide-type control. Accordingly, IL-22−/− mice showed more severe colonic damage.84 Adoptive transfer of IL-22-deficient CD45RBhi T cells to Il22−/−RAG−/− double KO mice resulted in exacerbated colitis when compared to control.85 IL-22 signals by binding to its heterodimer receptor, which is consisted of IL-10R2 and IL-22R1. Mutations in the IL-10R2 receptor have been demonstrated to be positively correlated with IBD (Table 1).86 The limited expression of IL-22R1 enables IL-22 to target nonhematopoietic cells such as epithelial cells.87 It has been demonstrated that IL-22 limited the extracellular bacteria through induction of intestinal epithelial cells to produce different antimicrobial peptides including S100 protein family (S100A7, S100A8 and S100A9) 75, 84, β-defensin protein family (hBD-2), Reg protein family (RegIIIβ and RegIIIγ)88 and lipocalin-2.89 Of note, IL-22 can further enhance the IL-17A or IL-17F–mediated antimicrobial peptides secretion.75

Author Manuscript

In consistence with the enhanced expression of MUC4 in IL-22-treated human intestinal epithelial cell line,75 local IL-22 gene delivery to the inflamed colonic tissues preserved the mucus layer of TCRα−/− mice and alleviated the chronic colitis. Moreover, blockade of IL-22 prevented the restitution of goblet cells during the recovery phase of DSS-driven colitis, which increased the susceptibility of host to intestinal infection.90 Gene chip analysis in combination with qPCR revealed activation of genes associated with proliferation, wound healing and anti-apoptosis downstream of IL-22, suggesting an essential role of IL-22 in tissue protection (Figure 2).91 More recently, IL-22 has been shown to promote intestinal stem cell-mediated epithelial regeneration through activation of STAT3.92

IL-26 in protection of intestinal inflammation

Author Manuscript

Until recently, Th17 cells were thought to engage in bactericidal defense indirectly via interaction with epithelial cells; however, a recent report demonstrates that Th17 cell supernatants directly restrain the growth of P. aeruginosa, and this effect is demonstrated to be IL-26-dependent.93 IL-26, another member of IL-10 cytokine family has been identified to be expressed by human Th17 cells, but has not been identified in mice.76 Genome-wide association studies (GWAS) revealed that SNPs in IL-26 gene is associated with IBD.94 Also, elevated IL-26 is found in inflamed lesions of IBD patients (Table 1).95 The characteristic cationic and amphipathic structure of IL-26 suggests a similar function like other antimicrobial peptides such as LL-37. Indeed, recombinant IL-26 decreased the bacterial load of Klebsiella pneumoniae infected mice. In vitro studies also demonstrate the efficacy of IL-26 inhibiting the growth and/or colony formation of both gram-negative bacteria and gram-positive bacteria via pore formation. In addition, Th17-derived IL-26 is able to form potent immunogenic complex with fragments of either bacteria DNA or host self-DNA to stimulate IFN-α production in plasmacytoid dendritic cells (pDCs), signifying the potential role of Th17 cells in antiviral defense.93 However, little effect of IL-26 on

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 11

Author Manuscript

Enterococcus faecalis and fungus Candida albicans suggests that further studies are needed to better understand the mechanisms of IL-26-mediated killing.

Th17 transdifferentiation into Tr1 cells

Author Manuscript

Th17 cells are not stable, and can cease to express their signature cytokine IL-17 as well as start expressing cytokines typical of other lineages under certain conditions, which has been associated with pathogenicity.96 An elegant recent study, by using novel fate-mapping mouse models to track TH17 cells during immune responses, showed that CD4+ T cells that formerly expressed IL-17 acquired an anti-inflammatory phenotype.97 The transdifferentiation of Th17 into regulatory T cells was demonstrated by changing their signature transcriptional profile and the acquisiting potent regulatory capacity. Even in steady state, about 50% of T cells which had expressed IL-17 previously (exTh17 cells) no longer expressed this cytokine, indicating that Th17 cells were not stable under even steady conditions. Interestingly, some of exTh17 cells expressed IL-10, which resemble Tr1 cells rather Th17 cells. Conversion of Th17 into Tr1 cells also occurred during the immune responses stimulated by anti-CD3 monoclonal antibody. Those Tr1 cells converted from exTh17 cells underwent transcriptional reprogramming during their conversion, which are similar to transcriptional programs of classic Tr1 cells rather than that of Th17 cells. When co-transferred into RAG−/− mice, Tr1 cells converted from exTh17 cells inhibited Th17 cellmediated colitis, indicating that those T cells are functionally regulatory cells. Thus, Th17 cells can physiologically transdifferentiate into regulatory T cells, and functionally inhibit intestinal inflammation induced by Th17 cells.97

Conclusions Author Manuscript Author Manuscript

Accumulating evidence indicates that the role of Th17 cells in IBD is more complicated than we originally thought, as they function both pro-inflammatorily and anti-inflammatorily under various conditions, which also raises the questions if there are still therapeutic opportunities in regulating Th17 cell and its pathways for IBD. Several points have to be taken considerations in this regard. 1) IL-17 ≠Th17. Upon activation by microbiota antigens, intestinal Th17 cells produce several signature cytokines. Il-17 is just one of them. Failure of clinic trails in CD by neutralizing IL-17 signaling does not necessarily mean the dearth of therapy in IBD through manipulating Th17 cells. 2) IL-23 ≠Th17. Looking back, most provailing data showing that Th17 cell mediate colitis development is most likely the reflection of the function of IL-23. However, IL-23 does not only promote Th17 cells, but also function in many other cells, including Treg cells, innate lymphocytes (ILC), and neutrophils, among others. 3) Simultaneously blocking pro-inflammatory Th17 cytokines and promoting tissue repair. Proper wound healing and epithelial restitution are required for recovery of intestinal inflammation. However, most strategies currently used for inhibition of pro-inflammatory cytokines in treatment of IBD have also generated an unexpected side effect of decreasing critical tissue repair factors, such as IL-22 and IL-6. It is worth thinking to simultaneously deliver the reagents blocking pro-inflammatory Th17 cytokines and factors promoting epithelial tissue repairs, such as IL-22 or low level of IL-6. Among many reasons in ineffectiveness of clinic trials with blocking IL-6 pathway in treatment of IBD, decreased IL-6 signaling might as well inhibit tissue repairs in addition to suppress its pro-

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 12

Author Manuscript

inflammatory effects. 4) Targeting upstream pathways of Th17 cells. If it is not beneficial by just targeting Th17 cytokines, we may consider to targeting upstream pathways of Th17 cells. For example, RORγt is required for Th17 cell development. Small molecule RORγt antagonists have been developed by several groups, and prevailing data have been reported in inhibiting several experimental autoimmune diseases by such RORγt antagonists.98, 99 It will be curious to see if such RORγt inhibitors can also function in inhibiting colitis, which will target Th17 cells but not just IL-17. 5) Targeting T cells expressing both IL-17 and IFNγ. Emerging data indicate that IL-17- and IFNγ-double expressing T cells are the pathogenic T cells in IBD, although the data is still lacking regarding if IL-17 and IFNγ are required for induction of colitis by such T cells. It could be beneficial to develop reagents which are able to inhibit the development of IL-17- and IFNγ-double expressing T cells.

Acknowledgments Author Manuscript

This work was supported by NIH grants DK098370 and DK105585.

Reference

Author Manuscript Author Manuscript

1. Elson CO, Cong Y. Host-microbiota interactions in inflammatory bowel disease. Gut Microbes. 2012; 3:332–344. [PubMed: 22572873] 2. Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008; 134:577– 594. [PubMed: 18242222] 3. Powrie F, Correa-Oliveira R, Mauze S, et al. Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cellmediated immunity. J Exp Med. 1994; 179:589–600. [PubMed: 7905019] 4. Singh B, Read S, Asseman C, et al. Control of intestinal inflammation by regulatory T cells. Immunol Rev. 2001; 182:190–200. [PubMed: 11722634] 5. Cong Y, Brandwein SL, McCabe RP, et al. CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease. J Exp Med. 1998; 187:855–864. [PubMed: 9500788] 6. Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006; 126:1121–1133. [PubMed: 16990136] 7. Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebocontrolled trial. Gut. 2012; 61:1693–1700. [PubMed: 22595313] 8. Symons A, Budelsky AL, Towne JE. Are Th17 cells in the gut pathogenic or protective? Mucosal Immunol. 2012; 5:4–6. [PubMed: 22071661] 9. Pennington DJ, Vermijlen D, Wise EL, et al. The integration of conventional and unconventional T cells that characterizes cell-mediated responses. Adv Immunol. 2005; 87:27–59. [PubMed: 16102571] 10. Pennington DJ, Silva-Santos B, Hayday AC. Gammadelta T cell development--having the strength to get there. Curr Opin Immunol. 2005; 17:108–115. [PubMed: 15766668] 11. Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986; 136:2348–2357. [PubMed: 2419430] 12. Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nat Rev Immunol. 2002; 2:933– 944. [PubMed: 12461566] 13. Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005; 6:1123–1132. [PubMed: 16200070]

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 13

Author Manuscript Author Manuscript Author Manuscript Author Manuscript

14. Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005; 6:1133–1141. [PubMed: 16200068] 15. Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003; 421:744–748. [PubMed: 12610626] 16. Murphy CA, Langrish CL, Chen Y, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003; 198:1951–1957. [PubMed: 14662908] 17. Ostanin DV, Bao J, Koboziev I, et al. T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade. Am J Physiol Gastrointest Liver Physiol. 2009; 296:G135– G146. [PubMed: 19033538] 18. Sundberg JP, Elson CO, Bedigian H, et al. Spontaneous, heritable colitis in a new substrain of C3H/HeJ mice. Gastroenterology. 1994; 107:1726–1735. [PubMed: 7958684] 19. Brandwein SL, McCabe RP, Cong Y, et al. Spontaneously colitic C3H/HeJBir mice demonstrate selective antibody reactivity to antigens of the enteric bacterial flora. J Immunol. 1997; 159:44–52. [PubMed: 9200437] 20. Feng T, Wang L, Schoeb TR, et al. Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis. J Exp Med. 2010; 207:1321–1332. [PubMed: 20498021] 21. Lodes MJ, Cong Y, Elson CO, et al. Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest. 2004; 113:1296–1306. [PubMed: 15124021] 22. Elson CO, Cong Y. Understanding immune-microbial homeostasis in intestine. Immunol Res. 2002; 26:87–94. [PubMed: 12403348] 23. Probert CS, Chott A, Turner JR, et al. Persistent clonal expansions of peripheral blood CD4+ lymphocytes in chronic inflammatory bowel disease. J Immunol. 1996; 157:3183–3191. [PubMed: 8816432] 24. Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest. 2007; 117:514–521. [PubMed: 17332878] 25. Mannon PJ, Fuss IJ, Mayer L, et al. Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med. 2004; 351:2069–2079. [PubMed: 15537905] 26. Witowski J, Pawlaczyk K, Breborowicz A, et al. IL-17 stimulates intraperitoneal neutrophil infiltration through the release of GRO alpha chemokine from mesothelial cells. J Immunol. 2000; 165:5814–5821. [PubMed: 11067941] 27. Weaver CT, Elson CO, Fouser LA, et al. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol. 2013; 8:477–512. [PubMed: 23157335] 28. Behnsen J, Jellbauer S, Wong CP, et al. The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity. 2014; 40:262–273. [PubMed: 24508234] 29. Rutz S, Eidenschenk C, Ouyang W. IL-22, not simply a Th17 cytokine. Immunol Rev. 2013; 252:116–132. [PubMed: 23405899] 30. Mangan PR, Harrington LE, O’Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006; 441:231–234. [PubMed: 16648837] 31. Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007; 448:484–487. [PubMed: 17581588] 32. Gaffen SL, Jain R, Garg AV, et al. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol. 2014; 14:585–600. [PubMed: 25145755] 33. Elson CO, Cong Y, Weaver CT, et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology. 2007; 132:2359–2370. [PubMed: 17570211] 34. Korn T, Bettelli E, Oukka M, et al. IL-17 and Th17 Cells. Annu Rev Immunol. 2009; 27:485–517. [PubMed: 19132915] 35. Ghoreschi K, Laurence A, Yang XP, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature. 2010; 467:967–971. [PubMed: 20962846] 36. Lee Y, Awasthi A, Yosef N, et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol. 2012; 13:991–999. [PubMed: 22961052] 37. Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009; 139:485–498. [PubMed: 19836068]

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 14

Author Manuscript Author Manuscript Author Manuscript Author Manuscript

38. Sano T, Huang W, Hall JA, et al. An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses. Cell. 2015; 163:381–393. [PubMed: 26411290] 39. Lecuyer E, Rakotobe S, Lengline-Garnier H, et al. Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses. Immunity. 2014; 40:608–620. [PubMed: 24745335] 40. Geuking MB, Cahenzli J, Lawson MA, et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity. 2011; 34:794–806. [PubMed: 21596591] 41. Goto Y, Panea C, Nakato G, et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity. 2014; 40:594–607. [PubMed: 24684957] 42. Yang Y, Torchinsky MB, Gobert M, et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature. 2014; 510:152–156. [PubMed: 24739972] 43. Uematsu S, Fujimoto K, Jang MH, et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat Immunol. 2008; 9:769–776. [PubMed: 18516037] 44. Scott CL, Tfp ZM, Beckham KS, et al. Signal regulatory protein alpha (SIRPalpha) regulates the homeostasis of CD103(+) CD11b(+) DCs in the intestinal lamina propria. Eur J Immunol. 2014; 44:3658–3668. [PubMed: 25236797] 45. Murugaiyan G, da Cunha AP, Ajay AK, et al. MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis. J Clin Invest. 2015; 125:1069–1080. [PubMed: 25642768] 46. Mycko MP, Cichalewska M, Machlanska A, et al. MicroRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination. Proc Natl Acad Sci U S A. 2012; 109:E1248–E1257. [PubMed: 22517757] 47. Xue X, Feng T, Yao S, et al. Microbiota downregulates dendritic cell expression of miR-10a, which targets IL-12/IL-23p40. J Immunol. 2011; 187:5879–5886. [PubMed: 22068236] 48. Wu W, He C, Liu C, et al. miR-10a inhibits dendritic cell activation and Th1/Th17 cell immune responses in IBD. Gut. 2015; 64:1755–1764. [PubMed: 25281418] 49. Feng T, Qin H, Wang L, et al. Th17 cells induce colitis and promote Th1 cell responses through IL-17 induction of innate IL-12 and IL-23 production. J Immunol. 2011; 186:6313–6318. [PubMed: 21531892] 50. Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003; 52:65–70. [PubMed: 12477762] 51. Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut. 2008; 57:1682–1689. [PubMed: 18653729] 52. Sakuraba A, Sato T, Kamada N, et al. Th1/Th17 Immune Response is Induced by Mesenteric Lymph Node Dendritic Cells in Crohn’s Disease. Gastroenterology. 2009; 137:1736–1745. [PubMed: 19632232] 53. Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006; 116:1310–1316. [PubMed: 16670770] 54. Leppkes M, Becker C, Ivanov II, et al. RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology. 2009; 136:257–267. [PubMed: 18992745] 55. Ahern PP, Schiering C, Buonocore S, et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity. 2010; 33:279–288. [PubMed: 20732640] 56. Uhlig HH, McKenzie BS, Hue S, et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity. 2006; 25:309–318. [PubMed: 16919486] 57. Lee YK, Turner H, Maynard CL, et al. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009; 30:92–107. [PubMed: 19119024] 58. Harbour SN, Maynard CL, Zindl CL, et al. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A. 2015; 112:7061–7066. [PubMed: 26038559]

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 15

Author Manuscript Author Manuscript Author Manuscript Author Manuscript

59. Globig AM, Hennecke N, Martin B, et al. Comprehensive intestinal T helper cell profiling reveals specific accumulation of IFN-gamma+IL-17+coproducing CD4+ T cells in active inflammatory bowel disease. Inflamm Bowel Dis. 2014; 20:2321–2329. [PubMed: 25248005] 60. Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006; 314:1461–1463. [PubMed: 17068223] 61. McGovern DP, Kugathasan S, Cho JH. Genetics of Inflammatory Bowel Diseases. Gastroenterology. 2015; 149:1163–1176. e2. [PubMed: 26255561] 62. Cosmi L, De Palma R, Santarlasci V, et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J Exp Med. 2008; 205:1903–1916. [PubMed: 18663128] 63. Brand S, Beigel F, Olszak T, et al. IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2006; 290:G827–G838. [PubMed: 16537974] 64. Kamada N, Hisamatsu T, Okamoto S, et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest. 2008; 118:2269–2280. [PubMed: 18497880] 65. Fuss IJ, Neurath M, Boirivant M, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease Crohn’s disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996; 157:1261–1270. [PubMed: 8757634] 66. Heller F, Florian P, Bojarski C, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005; 129:550–564. [PubMed: 16083712] 67. Shih VF, Cox J, Kljavin NM, et al. Homeostatic IL-23 receptor signaling limits Th17 response through IL-22-mediated containment of commensal microbiota. Proc Natl Acad Sci U S A. 2014; 111:13942–13947. [PubMed: 25201978] 68. O’Connor W Jr, Kamanaka M, Booth CJ, et al. A protective function for interleukin 17A in T cellmediated intestinal inflammation. Nat Immunol. 2009; 10:603–609. [PubMed: 19448631] 69. Song X, Dai D, He X, et al. Growth Factor FGF2 Cooperates with Interleukin-17 to Repair Intestinal Epithelial Damage. Immunity. 2015; 43:488–501. [PubMed: 26320657] 70. Lee JS, Tato CM, Joyce-Shaikh B, et al. Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability. Immunity. 2015; 43:727–738. [PubMed: 26431948] 71. Maxwell JR, Zhang Y, Brown WA, et al. Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation. Immunity. 2015; 43:739–750. [PubMed: 26431947] 72. Cao AT, Yao S, Gong B, et al. Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J Immunol. 2012; 189:4666–4673. [PubMed: 22993206] 73. Cai S, Batra S, Langohr I, et al. IFN-gamma induction by neutrophil-derived IL-17A homodimer augments pulmonary antibacterial defense. Mucosal Immunol. 2015 74. Taylor PR, Roy S, Leal SM Jr, et al. Activation of neutrophils by autocrine IL-17A–IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORgammat and dectin-2. Nat Immunol. 2014; 15:143–151. [PubMed: 24362892] 75. Liang SC, Tan XY, Luxenberg DP, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006; 203:2271– 2279. [PubMed: 16982811] 76. Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007; 8:950–957. [PubMed: 17676044] 77. Ye P, Rodriguez FH, Kanaly S, et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med. 2001; 194:519–527. [PubMed: 11514607] 78. Hammarstrom L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol. 2000; 120:225–231. [PubMed: 10792368] 79. Hirota K, Turner JE, Villa M, et al. Plasticity of Th17 cells in Peyer’s patches is responsible for the induction of T cell-dependent IgA responses. Nat Immunol. 2013; 14:372–379. [PubMed: 23475182]

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 16

Author Manuscript Author Manuscript Author Manuscript Author Manuscript

80. Cao AT, Yao S, Gong B, et al. Interleukin (IL)-21 promotes intestinal IgA response to microbiota. Mucosal Immunol. 2015; 8:1072–1082. [PubMed: 25586558] 81. Avery DT, Bryant VL, Ma CS, et al. IL-21-induced isotype switching to IgG and IgA by human naive B cells is differentially regulated by IL-4. J Immunol. 2008; 181:1767–1779. [PubMed: 18641314] 82. Yeste A, Mascanfroni ID, Nadeau M, et al. IL-21 induces IL-22 production in CD4+ T cells. Nat Commun. 2014; 5:3753. [PubMed: 24796415] 83. Wolk K, Witte E, Hoffmann U, et al. IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn’s disease. J Immunol. 2007; 178:5973– 5981. [PubMed: 17442982] 84. Zindl CL, Lai JF, Lee YK, et al. IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc Natl Acad Sci U S A. 2013; 110:12768–12773. [PubMed: 23781104] 85. Zenewicz LA, Yancopoulos GD, Valenzuela DM, et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008; 29:947–957. [PubMed: 19100701] 86. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009; 361:2033–2045. [PubMed: 19890111] 87. Ouyang W. Distinct roles of IL-22 in human psoriasis and inflammatory bowel disease. Cytokine Growth Factor Rev. 2010; 21:435–441. [PubMed: 21106435] 88. Fukui H, Sekikawa A, Tanaka H, et al. DMBT1 is a novel gene induced by IL-22 in ulcerative colitis. Inflamm Bowel Dis. 2011; 17:1177–1188. [PubMed: 20824812] 89. Raffatellu M, George MD, Akiyama Y, et al. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe. 2009; 5:476–486. [PubMed: 19454351] 90. Sugimoto K, Ogawa A, Mizoguchi E, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008; 118:534–544. [PubMed: 18172556] 91. Pickert G, Neufert C, Leppkes M, et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med. 2009; 206:1465–1472. [PubMed: 19564350] 92. Lindemans CA, Calafiore M, Mertelsmann AM, et al. Interleukin-22 promotes intestinal-stem-cellmediated epithelial regeneration. Nature. 2015; 528:560–564. [PubMed: 26649819] 93. Meller S, Di Domizio J, Voo KS, et al. T(H)17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26. Nat Immunol. 2015; 16:970–979. [PubMed: 26168081] 94. Silverberg MS, Cho JH, Rioux JD, et al. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet. 2009; 41:216–220. [PubMed: 19122664] 95. Dambacher J, Beigel F, Zitzmann K, et al. The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut. 2009; 58:1207–1217. [PubMed: 18483078] 96. Hirota K, Duarte JH, Veldhoen M, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011; 12:255–263. [PubMed: 21278737] 97. Gagliani N, Vesely MC, Iseppon A, et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature. 2015; 523:221–225. [PubMed: 25924064] 98. Skepner J, Ramesh R, Trocha M, et al. Pharmacologic inhibition of RORgammat regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo. J Immunol. 2014; 192:2564–2575. [PubMed: 24516202] 99. Solt LA, Kumar N, Nuhant P, et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature. 2011; 472:491–494. [PubMed: 21499262]

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 17

Author Manuscript Author Manuscript Figure 1. Subsets of CD4+ T cells

Author Manuscript

Upon antigen stimulation, naïve CD4+ T cells differentiate into Th1, Th2, Th17 and regulatory T cells under certain cytokine cues. IL-12 stimulates development of Th1 cells, which produce signature cytokine IFNγ; IL-4 stimulates naïve T cells development into Th2 cells, which produce IL-4, IL-5 and IL-13. TGFβ alone promotes Treg cells, whereas stimulates Th17 cells together with IL-6. Both Th1 and Th17 cells mediate the pathogenesis of Crohn’e Disease (CD) and ulcerative colitis (UC), while Th2, and possibly Th17 cells, mediate UC. Treg cells inhibit effector T cell function in CD and UC.

Author Manuscript Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Wei et al.

Page 18

Author Manuscript Author Manuscript Author Manuscript

Figure 2. Th17 cell protection in the intestines

Th17 cells protect the intestines from inflammation upon inflammatory insults through production of various cytokines. IL-17 promotes intestinal epithelial cell proliferation and enhances epithelial barrier function, as well as stimulates epithelial cell production of antimicrobial peptides and induces pIgR expression, which translocates IgA into intestinal lumen. IL-21 directly induces B cell CSR and promotes IgA production. IL-22 promotes intestinal tissue repair and wood healing probably through induction of stem cell proliferation. Th17 can also transdifferentiate into Tr1 cells, which in turn inhibit inflammatory function of Th17 cells.

Author Manuscript Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Author Manuscript

Author Manuscript

Author Manuscript IL-12p40 IL2/IL21 IL-26 CCL11 CCL20 IRF8 STAT3

IL12B

IL26

CCL11

CCL20

IRF8

STAT3

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

IL2/IL21

IL-23R

IL23R

CD/UC

CD/UC

IL-10R2

IL10R2

UC

CD/UC

AHR HNF4A

AHR

HNF4A

UC

IRF5

IRF5

UC

IRF4

IRF4

CD NFAT1

CD27

CD27

CD

NFATC1

CCR6R (CD196)

CCR6

CD

CD

Encoded protein

Gene/locus

Disease

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

CD/UC

Disease

VDR

MUC19

MAP3K8

ATF4

NFIL3

ICOSLG

SOCS1

CEBPB

CARD9

TYK2

JAK2

SMAD7

SMAD3

TNFSF15

RORC

Gene/locus

VDR

MUC19

MAP3K8

ATF4

NFIL3

ICOS ligand

SOCS1

CEBPβ

CARD9

TYK2

JAK2

SMAD7

SMAD3

TL1A

RORγ

Encoded protein

Immune gene variants linked to Th17 pathway in inflammatory bowel disease

Author Manuscript

Table 1 Wei et al. Page 19

Inflamm Bowel Dis. Author manuscript; available in PMC 2017 June 01.

Microbiota-specific Th17 Cells: Yin and Yang in Regulation of Inflammatory Bowel Disease.

Multiple mechanisms are involved in regulation of host response to microbiota to maintain the intestinal homeostasis. Th17 cells are enriched in the i...
643KB Sizes 2 Downloads 9 Views