Next Article in Journal
Identification of Lymphatic and Hematogenous Routes of Rapidly Labeled Radioactive and Fluorescent Exosomes through Highly Sensitive Multimodal Imaging
Next Article in Special Issue
AHR Signaling Interacting with Nutritional Factors Regulating the Expression of Markers in Vascular Inflammation and Atherogenesis
Previous Article in Journal
Heterogeneous Presynaptic Distribution of Munc13 Isoforms at Retinal Synapses and Identification of an Unconventional Bipolar Cell Type with Dual Expression of Munc13 Isoforms: A Study Using Munc13-EXFP Knock-in Mice
Previous Article in Special Issue
Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 21
Issue 21
10.3390/ijms21217849
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

From Suppressor T Cells to Regulatory T Cells: How the Journey that Began with the Discovery of the Toxic Effects of TCDD Led to Better Understanding of the Role of AhR in Immunoregulation

by
Narendra Prasad Singh
,
Mitzi Nagarkatti
and
Prakash Nagarkatti
*
Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(21), 7849; https://doi.org/10.3390/ijms21217849
Submission received: 28 September 2020 / Revised: 20 October 2020 / Accepted: 21 October 2020 / Published: 22 October 2020
(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)
Browse Figure
Versions Notes

Abstract

:
Aryl hydrocarbon receptor (AhR) was identified in the early 1970s as a receptor for the ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), which is a member of halogenated aromatic hydrocarbons (HAHs). TCDD was found to be highly toxic to the immune system, causing thymic involution and suppression of a variety of T and B cell responses. The fact that environmental chemicals cause immunosuppression led to the emergence of a new field, immunotoxicology. While studies carried out in early 1980s demonstrated that TCDD induces suppressor T cells that attenuate the immune response to antigens, further studies on these cells were abandoned due to a lack of specific markers to identify such cells. Thus, it was not until 2001 when FoxP3 was identified as a master regulator of Regulatory T cells (Tregs) that the effect of AhR activation on immunoregulation was rekindled. The more recent research on AhR has led to the emergence of AhR as not only an environmental sensor but also as a key regulator of immune response, especially the differentiation of Tregs vs. Th17 cells, by a variety of endogenous, microbial, dietary, and environmental ligands. This review not only discusses how the role of AhR emerged from it being an environmental sensor to become a key immunoregulator, but also confers the identification of new AhR ligands, which are providing novel insights into the mechanisms of Treg vs. Th17 differentiation. Lastly, we discuss how AhR ligands can trigger epigenetic pathways, which may provide new opportunities to regulate inflammation and treat autoimmune diseases.

1. Introduction

Aryl hydrocarbon receptor (AhR) belongs to the family of basic helix–loop–helix transcription factors [1]. It was first discovered in the early 1970s for its ability to bind 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) with high affinity [2] and induce a xenobiotic-metabolizing enzyme known as aryl hydrocarbon hydroxylase (AHH). TCDD, also known as dioxin, is an environmental contaminant that binds to AhR with high affinity. In the early 1970s, toxicologists also became aware of the fact that environmental contaminants can suppress the immune response leading to the emergence of a new field, immunotoxicology. In one of the early studies published in 1973, Vos et al., demonstrated that TCDD suppressed humoral and cell-mediated immunity [3]. These studies led to additional research all over the world exploring the effect of environmental pollutants and chemicals on the immune system, to address the concern that such compounds, by suppressing the immune response, may also make people more susceptible to infections and cancer. The authors of this review as well as several others were some of the early investigators who demonstrated how various chemicals used in the environment and industry could modulate the immune response, which also led to the establishment of immunological assays to screen for immunotoxicity [4,5,6,7,8].
Historically, it is exciting to know how the field of immunotoxicology, which began with the studies on TCDD and its receptor AhR leading to immunomodulation, also led more recently to characterization of natural and environmental ligands for AhR, and an understanding of how AhR activation triggers the regulation of T cell differentiation. Thus, within the span of 4 decades, the critical role of AhR is beginning to emerge, suggesting that it not only serves as an environmental sensor but also a key transcription factor that regulates several genes, especially those associated with the regulation of inflammation, leading to control of Regulatory T cells (Tregs) and inflammatory Th17 cells. It is very interesting to note that while the role of AhR in the field of toxicology was continuously developed though major advances in understanding how it regulated toxicity, its role in the field of immunology lagged behind in those 4 decades due to deficiencies in identifying the T cell subsets, especially the Tregs. Nonetheless, early studies on immunosuppressive effects of TCDD through activation of AhR set the stage for understanding the role of AhR in immunoregulation. Thus, this review highlights how the discovery of AhR in the field of immunotoxicology contributed towards better understanding of this transcription factor and its potential use in regulating inflammatory and autoimmune diseases.

2. TCDD Causes Toxicity and Immunosuppression through AhR: Early Studies

Since the discovery of AhR and its ligand TCDD, almost 45 years ago, there have been several studies trying to understand the nature of TCDD-induced toxicity in animals and humans [9,10,11,12,13,14,15,16,17,18,19,20,21]. Early reports suggested that TCDD not only caused overt toxicity in animals and but also caused immunosuppression [9,10,11,12,13,14,15,16,17,18,19,20,21]. Later, it was shown that TCDD acted through AhR present on a variety of immune cells [9,10,11,12,13,14,15,16,17,18,19,20,21].
As early as 1981, Clark et al. found that TCDD was very toxic, and, at a dose of 100 μg/kg or greater, produced cellular depletion in thymus, spleen, and lymph nodes in mice [22]. Moreover, the antibody responses to Sheep Red Blood Cells (SRBC) and TNP-Brucella abortus, as well as the delayed type hypersensitivity (DTH) response to oxazalone, were impaired following treatment with TCDD. TCDD caused a decrease in cytotoxic T lymphocyte (CTL) activity and in vitro analysis of the mechanism of suppression demonstrated that TCDD did not alter the precursor cells of CTL, but induced cells that could suppress CTL generation in vitro [22]. In 1984, one of the co-authors of this review, working in the Clark laboratory, reported that TCDD-induced susceptibility of mice to a variety of immunotoxic effects was genetically dictated by the presence of AhR locus [23]. In this report, it was shown that TCDD suppressed the generation of allo-specific CTL in the “susceptible” C57Bl/6 (Ahb), but not in “resistant” DBA-2(Ahd) [23]. To determine if TCDD acted directly on the “susceptible” lymphoid cells, the authors developed bone-marrow chimeras and found that the susceptibility to immunosuppression caused by TCDD in chimeric mice was influenced by the Ah genotype of the recipient host and not by the genotype of the donor’s grafted lymphomyeloid cells. Cell mixing experiments showed that the suppression of CTL generation by TCDD was caused by suppressor T cells [23]. These data were intriguing, and the recent observation that Tregs are relatively more radioresistant than other lymphocytes [24] may have led to this observation seen in chimeras.
Although early studies dating back to 1984 reported that TCDD caused the generation of “Suppressor T Cells” through the activation of AhR, it was difficult to identify these suppressor T cells due to a lack of specific cell markers. While some immunologists proposed that these suppressor cells express I-J molecules encoded by the Major Histocompatibility Complex (MHC), it was shown subsequently using molecular techniques that the I-J region did not exist in the MHC, which led to the rapid collapse of additional research on suppressor T cells [25]. Thus, unfortunately, further research that AhR activation by TCDD induces suppressor T cells was abandoned. It was not until 1995, when Sakaguchi et al. (1995) discovered T cells that suppressed immune response, which they called regulatory T cells (Tregs) [26], by identifying the expression of interleukin (IL)-2 receptor α-chain (CD25) on the cell surface of CD4+ T helper (Th) cell subtype, that the interest in T cells that could suppress immune response was once again ignited [26]. In 2001, T cells that suppress inflammation were further characterized with a specific biomarker, FoxP3, using scurfy mice that were devoid of this marker [27]. Bennet et al., in 2001, also reported that patients with the IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome) carried mutations in the FoxP3, which led to dysfunctional FoxP3 protein expression and patients not developing functional Tregs, leading to lymphoproliferative and autoimmune disease [28]. A few years later, another breakthrough came in 2003, when FoxP3 was identified as the main transcription factor driving and maintaining Treg phenotype and function [29,30,31]. TCDD-induced Tregs/suppressor T cells received renewed attention with the discovery of a biomarker, FoxP3, as described in other reviews [32], which led to several novel studies on the mechanisms through which AhR activation by TCDD induced Tregs [33,34,35,36,37]. Around this time, there were also reports suggesting that TCDD may induce CD25+CD4+ Tregs that are FoxP3− [38] or FoxP3+ [39], thereby suggesting that their induction may depend on the nature of the model and antigenic stimulation. Thus, identification of FoxP3 as a marker and master regulator of Tregs established the possible link between AhR and the regulation of inflammation and autoimmune disease. The focus of new studies was also to further understand the effect of TCDD on Treg subsets.

3. Tregs and Their Subsets

Studies revealed that Tregs belonged to two main subtypes: natural Tregs, which originate in the thymus (tTregs), and induced Tregs, which originate in the periphery (pTregs), following activation of naïve CD4+ T cells [25]. Although the term “regulatory T cell” was conventionally used to describe CD25+/FoxP3+ CD4+ T cells, it was shown that in the mouse, additional subtypes of Tregs could be demonstrated due to the lack or transient expression of FoxP3. For example, pTregs that produce high levels of IL-10 were classified as Tr1 (Treg type 1) cells, and Tregs producing high levels of TGF-β were classified as Th3 cells. Th3 cells can be FoxP3− and shown to suppress autoimmune colitis [40,41]. Furthermore, it was noted that stable expression of FoxP3 was essential for Treg function and was sustained through epigenetic regulation of both in the FoxP3 gene locus and Treg-specific demethylated region (TSDR) [42,43]. Naïve FoxP3− CD4+ T cells in the mouse can express FoxP3 in the presence of transforming growth factor β (TGF-β) or retinoic acid, which promotes the development of peripherally induced Tregs.

4. AhR Ligands and How They Impact the Differentiation of Tregs vs. Th17

In recent years, there has been a significant surge in studies demonstrating that AhR activation by its ligands, natural or synthetic, triggers molecular mechanisms leading to ligand-specific regulation/differentiation of not only Tregs but also Th17 cells [33,35,36,37,39,44,45]. A list of AhR ligands and their potential effects on the immune response has been shown in Table 1. First, AhR was shown to be highly expressed by both Tregs and Th17 cells [37,45,46,47,48], while other T cell subsets such as Th1 and Th2 may express little or no AhR [49], thereby suggesting that AhR may primarily affect Th17/Treg differentiation. In 2008, Quintana et al. reported the identification of the ligand-activated AhR as a regulator of Treg and Th17 cell differentiation in mice [35]. They reported that AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional Tregs that suppressed experimental autoimmune encephalomyelitis (EAE) in mice [35]. AhR activation by 6-formylindolo(3,2-b)carbazole (FICZ), on the other hand, interfered with Treg’s development, boosted Th17 cell differentiation, and increased the severity of EAE in mice [35]. They proposed that AhR regulates both Treg and Th17 cell differentiation and the type of T cell differentiation may depend on the nature of AhR ligand. Around the same time, Veldhoen et al. also reported that AhR activation by FICZ was capable of stimulating myelin-reactive Th17 cells in an EAE model. More importantly, they found that CD4+ T cells from AhR-deficient mice could still develop into Th17 cells, but they lacked IL-22 expression. Their study concluded that stimulation of AhR by an environmental toxin promotes IL-22 production and enhances Th17 development [50]. Thus, when Veldhoen et al. studied EAE in AhR-deficient mice, they noted delayed onset and less severe disease compared to wildtype mice, correlating with a lack of functional Th17 cells in AhR-deficient mice [50]. In contrast, Quintana et al. used AhRd mice with lower affinity binding of ligand to AhR, and found that these mice developed more severe forms of EAE than wildtype mice, which correlated with higher frequencies of Th17 cells [35]. The different responses seen in AhR-deficient mice versus those having AhR mutation (AhRd), which leads to decreased ligand affinity towards AhR, is intriguing and further suggests that ligand affinity or endogenous ligands present in AhRd mice play a role in regulating neuroinflammation in this model.
Studies from our lab showed that TCDD-induced activation of AhR promoted the generation of Tregs that suppressed experimental colitis in mice [37]. In this study, we also observed that FICZ, on the other hand, promoted generation of Th17 cells, leading to enhancement of experimental colitis in mice [37]. In another study, we reported that indoles such as Indole-3-carbinol (I3C), which act as dietary AhR ligands, also promoted the generation of Tregs, suppressed differentiation of Th17 cells, and mitigated EAE in mice [45]. Additionally, we noted that dietary indoles promoted Tregs differentiation and suppressed Th17 cells differentiation, leading to suppression of Delayed-Type Hypersensitivity (DTH) in mice [48]. It was shown that dietary indoles suppressed DTH by inducing a switch from proinflammatory Th17 cells to anti-inflammatory Tregs through the regulation of miRNA [48]. All such studies clearly demonstrated that AhR activation by its ligands promoted Tregs/Th17 cells differentiation in a ligand specific manner [33,35,36,37,39,44,45].
Indoleamine-pyrrole 2,3-dioxygenase (IDO) is a heme-containing enzyme involved in tryptophan metabolism involving the kynurenine pathway. It is involved not only in tryptophan deprivation but also in the production of immunoactive kynurenines, which act as AhR ligands. Mature dendritic cells (DCs) that express IDO have been shown to induce proliferation of CD4+CD25+FoxP3+ Tregs [51]. In addition, IDO has been shown to promote the activation of Tregs while preventing the differentiation of Th-17 cells [52]. Interestingly, blocking IDO was shown to prevent Tregs and promote the differentiation of Th17 cells [53]. Such studies suggested that kynurenine produced by IDO, which acts as AhR ligand, may be responsible for promoting Tregs while inhibiting Th17 differentiation. DCs express AhR and in fact AhR also plays a critical role in the induction of IDO. Thus, AhR-deficient mice lack IDO and hence fail to produce Tregs while inducing Th-17 cells. However, addition of synthetic kynurenine to the T cell cultures polarized T cell differentiation more towards Tregs when compared to Th17 cells [54]. Together, these studies suggested that there is cross talk between AhR and IDO, and that IDO, through the induction of kynurenine, may also regulate Treg vs. Th-17 differentiation.
AhR ligands have also been shown to exert both oxidative and antioxidative properties [55,56,57]. Such ligands have been studied extensively in skin cells, such as keratinocytes, because they express significant levels of AhR [57]. Environmental toxicants such as TCDD and benzo[α]pyrene, primarily induce reactive oxygen species (ROS) in keratinocytes via AhR activation [56]. Such toxicants induce CYP1A1 and ROS generation, leading to DNA damage as well as interleukin 8 (IL-8) production in keratinocytes, which may account for their carcinogenic properties, and IL-8-driven inflammatory skin disorders such as psoriasis and palmoplantar pustulosis, respectively [57]. In contrast, several phytochemicals act as anti-oxidant ligands, including sulforaphane, soybean tar, cynaropicrin, Opuntia ficus-indica extract, and the like [55,56]. While these compounds activate AhR and induce CYP1A1 like TCDD, they inhibit ROS generation via the activation of nuclear factor-erythroid 2-related factor-2 (NRF2), an antioxidant master transcription factor [56]. Activation of NRF2 induces the transcription of a variety of antioxidant enzymes. The precise mechanisms through which environmental toxicants, versus phytochemicals, mediate differential effects, such as oxidative or antioxidative properties, following AhR activation, remain to be further elucidated. Oxidative stress can also affect T cell differentiation. For example, oxidative stress has also been shown to activate mTORC1, which in turn can activate inflammatory Th17 cells through the activation of STAT3 and ROR-gt [58,59]. In contrast, AhR ligands such as the phytochemicals that act as antioxidants may suppress inflammation by inducing Tregs and suppressing Th17 cells [60,61].
The T cell differentiation during AhR activation may also be driven by the cytokine and signaling pathways induced. There are studies showing that transforming growth factor (TGF)-β1 may induce the differentiation of Treg cells [62,63,64], while TGF-β1 along with combination of IL-6 or IL-21 induces the differentiation of Th17 [65,66,67,68]. Xingxing Liu et al. showed the role of STAT3 in AhR-regulated generation/suppression of Th17/Tregs [69]. They demonstrated that STAT3 might cooperate with AhR to regulate the differentiation of Th17 and Treg cells [69].
While the precise mechanisms that lead to such contrasting effects of AhR ligands on Treg/Th17 differentiation remain unclear, this may depend on the dose and duration of AhR activation [70], affinity of the ligand, and epigenetic alterations such as induction of miRNA that trigger pro- or anti-inflammatory activities [37,48,71], and the nature of microbiota [72]. In addition, because of the plasticity of T cells, and reciprocal regulation of Tregs vs. Th17 cells, it is possible that AhR activation may lead to the differentiation of either of these subsets based on the nature of antigenic stimulation, and cytokines that are found in the microenvironment. For example, it was shown that at early stages of Th17 cells differentiation, AhR activation might convert Th17 cells into IL-10-producing immunosuppressive Tr1 cells [73]. For the development of inflammatory Th17 cells, exposure to IL-23 is crucial. Thus, exposure to this cytokine during AhR activation of T cells may lead to inflammatory Th17 induction while its absence could lead to the generation of Tr1 cells [73].
Upon ligand binding, AhR can activate both the DRE-dependent and the DRE-independent protein–protein interaction pathway, which can regulate gene expression. Thus, in one study using three types of AHR ligands: agonist, antagonist, and selective AHR modulators (SAhRMs) that activate the non-DRE mediated pathway without activating the DRE-driven responses, it was shown that Th17 differentiation was mediated by the DRE-dependent pathway, and Treg differentiation was inhibited by suppressing the non-DRE pathway [74]. Another possibility of differential T cell response may result from the fact that TCDD has been shown to induce Activation Induced Cell Death (AICD) through apoptosis involving Fas–FasL activation [37,45,46,47,48]. Thus, this process may lead to the loss of antigen-activated T cells, leading to increased proportions of Tregs.

5. Epigenetic Regulation of T Cell Differentiation and Inflammation Following AhR Activation

Several recent studies from our lab have shown that both AhR-ligands such as TCDD and FICZ caused epigenetic modifications by regulating the expression of microRNAs (miRNAs), DNA methylation (hypomethylation and/or hypermethylation), and histone modification in the promoters of FoxP3 and IL-17 [37,45,48,71], which may regulate their differentiation. For example, dietary indoles such as I3C or 3,3′-diindolylmethane(DIM) attenuated delayed-type hypersensitivity (DTH) response to methylated Bovine Serum Albumin (BSA) through the suppression of Th17 cells while enhancing Tregs [48]. In contrast, FICZ increased the DTH response by enhancing Th17 cells. Indoles decreased the induction of IL-17 but promoted IL-10 and FoxP3 expression. microRNA (miR) analysis showed that I3C and DIM attenuated the expression of several miRs (miR-31, miR-219, and miR-490) that targeted FoxP3, while increasing the expression of miR-495 and miR-1192 that targeted IL-17 [48]. Surprisingly, FICZ caused opposite effects on these miRs. These studies demonstrated for the first time that the effect of AhR ligands to induce Tregs vs. Th17 cells may depend on the nature of miRs that they induce [48]. The role of miRs in inducing Tregs was also seen in another study using TCDD and pertussis-toxin mediated inflammatory response [71]. Some miRs may also regulate the expression of AhR and thereby influence the immune response. For example, miR124 was shown to play a critical role in the regulation of the inflammatory response of Chronic Rhinosinusitis (CRS) with nasal polyps through negatively regulating AhR expression [75].
TCDD was also shown to suppress colitis through the induction of Tregs while suppressing Th17 cells, and this was found to be associated with demethylation of CpG islands of FoxP3 and increased methylation in IL-17 promoter [37]. Recently, our lab demonstrated that TCDD caused significant induction of myeloid-derived suppressor cells (MDSCs) through AhR activation and miR regulation [76]. Because MDSCs are known to induce Tregs [77], it is likely that this may serve as yet another mechanism through which AhR activation triggers Treg differentiation. Alpinetin, a flavonoid, was found to suppress colitis through upregulation of miR-302 and decreasing the expression of DNMT-1, and thereby the methylation of FoxP3 promoter in CD4+ T cells in mice, leading to the induction of Tregs [78]. Deletion of AhR in T cells was shown to attenuate colitis, which results from suppressed Th17 cell infiltration into the lamina propria [79]. In this model, miRNA analysis showed that while colitis increased the expression of the miR-212/132 cluster, in AhR (−/−) mice, this expression was decreased. In addition, miR-212/132(−/−) mice were highly resistant to colitis, which correlated with decreased Th17 cells and increased IL-10-producing CD4+ cells [79], thereby establishing a connection between these miRs and Tr1 regulatory cells. Moreover, AhR activation leading to Th17 differentiation has also been shown to depend on the miR-132/212 cluster [80]. Dietary AhR ligands such as indoles (I3C and DIM) were shown to effectively attenuate Staphylococcal enterotoxin B (SEB)-mediated inflammation and liver injury by decreasing the expression of miR-31, which targeted the apoptotic pathways in activated T cells [81]. I3C may also act through the regulation of gut microbiota, as shown in a recent study in which AhR activation by I3C led to increased production of butyrate and attenuation of colitis. Thus, when mice with colitis were given butyrate, there was a decrease in colonic inflammation resulting from the suppression of Th17 and the induction of Tregs [72]. Additionally, IL-22 was increased following treatment with I3C but not with butyrate, and neutralization of IL-22 blocked the beneficial effects of I3C against colitis [72]. This study suggested that I3C activation of AhR attenuates colitis primarily through the induction of IL-22, which leads to dysbiosis that promotes the production of anti-inflammatory butyrate [72]. In addition, I3C and DIM have also been shown to decrease SEB-mediated inflammation by acting as HDAC-I inhibitors [82]. Below (Table 1) is the list of AhR ligands and their ability to induce Tregs or Th17 cells
Table
Table 1. Natural and Synthetic AhR ligands and their effects on inflammation. It should be noted that some ligands may also act directly through other pathways such as NF-kB.
Table 1. Natural and Synthetic AhR ligands and their effects on inflammation. It should be noted that some ligands may also act directly through other pathways such as NF-kB.
AhR LigandsOrigin Synthetic/NaturalStructureEffect of AhR ligands on Inflammation and/or Tregs/Th17 Cells
2,3,7,8-Tetrachlorodibenzop-
dioxin (TCDD)		Exogenous/Synthetic Ijms 21 07849 i001Promotes Tregs, suppresses Th17 cells, and attenuates inflammation
[35,37]
ResveratrolDietary Ijms 21 07849 i002Promotes Tregs, suppresses Th17 cells, and attenuates inflammation
[83,84]
lndole-3-carbinol (I3C)Dietary Ijms 21 07849 i003Promotes Tregs, suppresses Th17 cells, attenuates inflammation, and inhibits NF-kB
[37,45]
3,3′-Diindolylmethane
(DIM)		Dietary Ijms 21 07849 i004Promotes Tregs, suppresses Th17 cells, and attenuates inflammation
[37,45]
Indolo[3,2-b]carbazole (ICZ)Dietary Ijms 21 07849 i005Attenuates inflammation [85,86]
lndole-3-acetonitrile (I3ACN)Dietary Ijms 21 07849 i006Anti-inflammatory and antioxidant [87]
2-(19H-indole-3′-carbonyl)-
thiazole-4-carboxylic acid
methyl ester (ITE)		Dietary Ijms 21 07849 i007Promotes Tregs, suppresses Th17 cells, and attenuates inflammation
[33,88]
2-(Indol-3-ylmethyl)-3,3′-
diindolylmethane (Ltr-1)		Dietary Ijms 21 07849 i008Attenuates inflammation [89,90]
IndoleMicrobial Ijms 21 07849 i009Promotes Tregs, suppresses Th17 cells, and attenuates inflammation
[37,45]
lndole-3-acetic acid (IAA)Microbial Ijms 21 07849 i010Anti-inflammatory and anti-oxidative [91,92]
lndole-3-aldehyde (IAld)Microbial Ijms 21 07849 i011Attenuates inflammation [93]
TryptamineMicrobial Ijms 21 07849 i012Attenuates inflammation [44,94]
3-Methyl-indole (skatole)Microbial Ijms 21 07849 i013Attenuates inflammation [95,96]
IndirubinMicrobial/host metabolism/Plants Ijms 21 07849 i014Promotes Tregs, suppresses Th17 cells, and attenuates inflammation
[97,98,99]
lndoxyl-3-sulfate (I3S)Microbial/host
metabolism		 Ijms 21 07849 i015Attenuates inflammation [100,101,102]
Kynurenine (Kyn)Host
metabolism		 Ijms 21 07849 i016Promotes Tregs and attenuates inflammation
[103]
Kynurenic acid (KA)Host
metabolism		 Ijms 21 07849 i017Promotes Tregs and attenuates inflammation
[103]
Xanthurenic acidHost
metabolism		 Ijms 21 07849 i018Anti-inflammatory
[94]
Cinnabarinic acid (CA)Host
metabolism		 Ijms 21 07849 i019Attenuates inflammation [104,105]
6-Formylindolo[3,2-b]carbazole (FICZ)Photo
oxidation		 Ijms 21 07849 i020Suppresses Tregs, promotes Th17 cells, inflammation
[35,37]

6. Conclusions

The aim of this review was to delineate how the current research involving the role of AhR in immunoregulation, specifically T cells, and its repercussion on the regulation of inflammatory and autoimmune diseases, originated from the field of immunotoxicology in the late 1970s and the early 1980s, when immunologists discovered that TCDD, an environmental pollutant, suppressed the immune response. While some studies clearly demonstrated in 1984 that TCDD triggered “suppressor T cells” [23], this observation did not receive further attention due to a lack of specific markers to identify these cells and distinguish them from other T cell subpopulations. Thus, the discovery of FoxP3 marker on CD4+ T cells, which led to the designation of the suppressor cells as Tregs, transformed the field, and immunologists began to unravel the mysteries of AhR not just as an environmental sensor involved in xenobiotic metabolism but also as a key regulator of immune functions.
The field has advanced significantly in the past decade through the discovery of a variety of natural and synthetic ligands of AhR, which is helping us to understand how pro- and anti-inflammatory T cells are regulated. The differential regulation of Th17 vs. Treg differentiation by various AhR ligands (proposed in Figure 1) still constitutes an enigma and needs additional research. Activation of AhR also leads to epigenetic modulations in T cells, and the question of how such effects in turn regulate Treg vs. Th17 differentiation is exciting and clearly deserves additional investigation. The role of AhR in inflammatory and autoimmune diseases, particularly in colitis and MS, is receiving significant recognition, which means that there is substantial opportunity to target AhR using ligands to prevent and treat inflammatory and autoimmune diseases.

Author Contributions

P.N. and M.N. conceived the idea for the manuscript. N.P.S. wrote the manuscript. P.N. and M.N. supervised from writing to finalizing the manuscript for journal submission. All authors have read and agreed to the published version of the manuscript.

Funding

These studies were supported in part by the National Institutes of Health (NIH) grants: P01AT003961, P20GM103641, R01AT006888, R01ES030144 and R01AI123947.

Conflicts of Interest

The authors have declared that no conflict of interest exist.

References

  1. Tian, Y.; Rabson, A.B.; Gallo, M.A. Ah receptor and NF-κB interactions: Mechanisms and physiological implications. Chem. Interact. 2002, 141, 97–115. [Google Scholar] [CrossRef]
  2. Poland, A.; Glover, E.; Kende, A.S. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J. Biol. Chem. 1976, 251, 4936–4946. [Google Scholar] [PubMed]
  3. Vos, J.G.; Moore, J.A.; Zinkl, J.G. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the immune system of laboratory animals. Environ. Heal. Perspect. 1973, 5, 149–162. [Google Scholar] [CrossRef] [PubMed]
  4. Boorman, G.A.; Luster, M.I.; Dean, J.H.; Campbell, M.L. Assessment of myelotoxicity caused by environmental chemicals. Environ. Heal. Perspect. 1982, 43, 129–135. [Google Scholar] [CrossRef]
  5. Dean, J.H.; Luster, M.I.; Boorman, G.A. Methods and approaches for assessing immunotoxicity: An overview. Environ. Heal. Perspect. 1982, 43, 27–29. [Google Scholar] [CrossRef] [PubMed]
  6. Kerkvliet, N.I.; Steppan, L.B.; Koller, L.D.; Exon, J.H. Immunotoxicology studies of sodium arsenate-effects of exposure on tumor growth and cell-mediated tumor immunity. J. Environ. Pathol. Toxicol. 1980, 4, 65. [Google Scholar] [PubMed]
  7. Nagarkatti, M.; Nagarkatti, P.S.; Raghuveeran, C. Short-term toxicity studies of O-chlorobenzylidene malononitrile on humoral immunity in mice. Toxicol. Lett. 1981, 8, 73–76. [Google Scholar] [CrossRef]
  8. Nagarkatti, P.S.; Nagarkatti, M. Effect ofo-chlorobenzylidenemalononitrile (CS) on humoral immune response to bacterial lipopolysaccharide in mice. Bull. Environ. Contam. Toxicol. 1981, 26, 571–575. [Google Scholar] [CrossRef]
  9. Blaylock, B.L.; Holladay, S.D.; Comment, C.E.; Heindel, J.J.; Luster, M.I. Exposure to tetrachlorodibenzo-p-dioxin (TCDD) alters fetal thymocyte maturation. Toxicol. Appl. Pharmacol. 1992, 112, 207–213. [Google Scholar] [CrossRef]
  10. Bock, K.W.; Köhle, C. Ah receptor: Dioxin-mediated toxic responses as hints to deregulated physiologic functions. Biochem. Pharmacol. 2006, 72, 393–404. [Google Scholar] [CrossRef]
  11. Camacho, I.A.; Nagarkatti, M.; Nagarkatti, P.S. 2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) induces Fas-dependent activation-induced cell death in superantigen-primed T cells. Arch. Toxicol. 2002, 76, 570–580. [Google Scholar] [CrossRef] [PubMed]
  12. Camacho, I.A.; Nagarkatti, M.; Nagarkatti, P.S. Effect of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) on maternal immune response during pregnancy. Arch. Toxicol. 2004, 78, 290–300. [Google Scholar] [CrossRef] [PubMed]
  13. Camacho, I.A.; Singh, N.; Hegde, V.L.; Nagarkatti, M.; Nagarkatti, P.S. Treatment of mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin leads to aryl hydrocarbon receptor-dependent nuclear translocation of NF-kappaB and expression of fas ligand in thymic stromal cells and consequent apoptosis in T cells. J. Immunol. 2005, 175, 90–103. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Dong, W.; Teraoka, H.; Kondo, S.; Hiraga, T. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin induces apoptosis in the dorsal midbrain of zebrafish embryos by activation of arylhydrocarbon receptor. Neurosci. Lett. 2001, 303, 169–172. [Google Scholar] [CrossRef]
  15. Fisher, M.T.; Nagarkatti, M.; Nagarkatti, P.S. 2,3,7,8-Tetrachlorodibenzo-p-dioxin Enhances Negative Selection of T Cells in the Thymus but Allows Autoreactive T Cells to Escape Deletion and Migrate to the Periphery. Mol. Pharmacol. 2004, 67, 327–335. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Holsapple, M.P.; Morris, D.L.; Wood, S.C.; Snyder, N.K. 2,3,7,8-Tetrachlorodibenzo-p-Dioxin-Induced Changes in Immunocompetence: Possible Mechanisms. Annu. Rev. Pharmacol. Toxicol. 1991, 31, 73–100. [Google Scholar] [CrossRef]
  17. Holsapple, M.P.; Snyder, N.K.; Wood, S.C.; Morris, D.L. A review of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced changes in immunocompetence: 1991 update. Toxicology 1991, 69, 219–255. [Google Scholar] [CrossRef]
  18. Lee, C.A.; Lawrence, B.; Kerkvliet, N.I.; Rifkind, A.B. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induction of cytochrome p450-dependent arachidonic acid metabolism in mouse liver microsomes: Evidence for species-specific differences in responses. Toxicol. Appl. Pharmacol. 1998, 153, 1–11. [Google Scholar] [CrossRef]
  19. Lundberg, K.; Dencker, L.; Grönvik, K.-O. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inhibits the activation of antigen-specific T-cells in mice. Int. J. Immunopharmacol. 1992, 14, 699–705. [Google Scholar] [CrossRef]
  20. Singh, N.P.; Nagarkatti, M.; Nagarkatti, P.S. Primary peripheral T cells become susceptible to 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated apoptosis in vitro upon activation and in the presence of dendritic cells. Mol. Pharmacol. 2008, 73, 1722–1735. [Google Scholar] [CrossRef] [Green Version]
  21. Singh, N.P.; Singh, U.P.; Guan, H.; Nagarkatti, P.S.; Nagarkatti, M. Prenatal exposure to TCDD Triggers significant modulation of microRNA expression profile in the thymus that affects consequent gene expression. PLoS ONE 2012, 7, e45054. [Google Scholar] [CrossRef]
  22. Clark, D.A.; Gauldie, J.; Szewczuk, M.R.; Sweeney, G. Enhanced suppressor cell activity as a mechanism of immunosuppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Exp. Biol. Med. 1981, 168, 290–299. [Google Scholar] [CrossRef]
  23. Nagarkatti, P.S.; Sweeney, G.D.; Gauldie, J.; Clark, D.A. Sensitivity to suppression of cytotoxic T cell generation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is dependent on the Ah genotype of the murine host. Toxicol. Appl. Pharmacol. 1984, 72, 169–176. [Google Scholar] [CrossRef]
  24. Kachikwu, E.L.; Iwamoto, K.S.; Liao, Y.-P.; Demarco, J.J.; Agazaryan, N.; Economou, J.S.; McBride, W.H.; Schaue, D. Radiation enhances regulatory t cell representation. Int. J. Radiat. Oncol. 2011, 81, 1128–1135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Sakaguchi, S.; Wing, K.; Miyara, M. Regulatory T cells–a brief history and perspective. Eur. J. Immunol. 2007, 37, S116–S123. [Google Scholar] [CrossRef] [PubMed]
  26. Sakaguchi, S.; Sakaguchi, N.; Asano, M.; Itoh, M.; Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 1995, 155, 1151–1164. [Google Scholar]
  27. Brunkow, M.E.; Jeffery, E.W.; Hjerrild, K.A.; Paeper, B.; Clark, L.B.; Yasayko, S.-A.; Wilkinson, J.E.; Galas, D.; Ziegler, S.F.; Ramsdell, F. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 2001, 27, 68–73. [Google Scholar] [CrossRef] [PubMed]
  28. Bennett, C.L.; Ochs, H.D. IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Curr. Opin. Pediatr. 2001, 13, 533–538. [Google Scholar] [CrossRef]
  29. Fontenot, J.D.; Gavin, M.A.; Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 2003, 4, 330–336. [Google Scholar] [CrossRef] [PubMed]
  30. Hori, S.; Nomura, T.; Sakaguchi, S. Control of Regulatory T Cell Development by the Transcription Factor Foxp3. Science 2003, 299, 1057–1061. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Khattri, R.; Cox, T.; Yasayko, S.-A.; Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 2003, 4, 337–342. [Google Scholar] [CrossRef]
  32. Marshall, N.B.; Kerkvliet, N.I. Dioxin and immune regulation. Ann. N. Y. Acad. Sci. 2010, 1183, 25–37. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Abron, J.D.; Singh, N.P.; Mishra, M.K.; Price, R.L.; Nagarkatti, M.; Nagarkatti, P.S.; Singh, U.P.; Abron, J.D. An endogenous aryl hydrocarbon receptor ligand, ITE, induces regulatory T cells and ameliorates experimental colitis. Am. J. Physiol. Liver Physiol. 2018, 315, G220–G230. [Google Scholar] [CrossRef] [PubMed]
  34. Boverhof, D.R.; Tam, E.; Harney, A.S.; Crawford, R.B.; Karmaus, P.W.F.; Zacharewski, T.R. 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Suppressor of Cytokine Signaling 2 in Murine B Cells. Mol. Pharmacol. 2004, 66, 1662–1670. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Quintana, F.J.; Basso, A.S.; Iglesias, A.H.; Korn, T.; Farez, M.F.; Bettelli, E.; Caccamo, M.; Oukka, M.; Weiner, H.L. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nat. Cell Biol. 2008, 453, 65–71. [Google Scholar] [CrossRef]
  36. Quintana, F.J.; Cohen, I.R. Regulatory T cells and immune computation. Eur. J. Immunol. 2008, 38, 903–907. [Google Scholar] [CrossRef]
  37. Singh, N.P.; Singh, U.P.; Singh, B.; Price, R.L.; Nagarkatti, M.; Nagarkatti, P.S. Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis. PLoS ONE 2011, 6, e23522. [Google Scholar] [CrossRef] [Green Version]
  38. Funatake, C.J.; Marshall, N.B.; Steppan, L.B.; Mourich, D.V.; Kerkvliet, N.I. Cutting edge: Activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin generates a population of CD4+CD25+ cells with characteristics of regulatory T cells. J. Immunol. 2005, 175, 4184–4188. [Google Scholar] [CrossRef] [Green Version]
  39. Kerkvliet, N.I.; Steppan, L.B.; Vorachek, W.; Oda, S.; Farrer, D.; Wong, C.P.; Pham, D.; Mourich, D. Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes. Immunotherapy 2009, 1, 539–547. [Google Scholar]
  40. Feng, T.; Cao, A.T.; Weaver, C.T.; Elson, C.O.; Cong, Y. Interleukin-12 Converts Foxp3+ Regulatory T Cells to Interferon–γ-Producing Foxp3+ T Cells That Inhibit Colitis. Gastroenterology 2011, 140, 2031–2043. [Google Scholar] [CrossRef] [Green Version]
  41. Groux, H.; O’Garra, A.; Bigler, M.; Rouleau, M.; Antonenko, S.; De Vries, J.E.; Roncarolo, M.G. A CD4+T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nat. Cell Biol. 1997, 389, 737–742. [Google Scholar] [CrossRef] [PubMed]
  42. Kouakanou, L.; Peters, C.; Sun, Q.; Floess, S.; Bhat, J.; Huehn, J.; Kabelitz, D. Vitamin C supports conversion of human γδ T cells into FOXP3-expressing regulatory cells by epigenetic regulation. Sci. Rep. 2020, 10, 1–13. [Google Scholar] [CrossRef] [PubMed]
  43. Polansky, J.K.; Kretschmer, K.; Freyer, J.; Floess, S.; Garbe, A.; Baron, U.; Olek, S.; Hamann, A.; Von Boehmer, H.; Huehn, J. DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 2008, 38, 1654–1663. [Google Scholar] [CrossRef] [PubMed]
  44. Ramirez, J.-M.; Brembilla, N.C.; Sorg, O.; Chicheportiche, R.; Matthes, T.; Dayer, J.-M.; Saurat, J.-H.; Roosnek, E.; Chizzolini, C. Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells. Eur. J. Immunol. 2010, 40, 2450–2459. [Google Scholar] [CrossRef]
  45. Rouse, M.; Singh, N.P.; Nagarkatti, P.S.; Nagarkatti, M. Indoles mitigate the development of experimental autoimmune encephalomyelitis by induction of reciprocal differentiation of regulatory T cells and Th17 cells. Br. J. Pharmacol. 2013, 169, 1305–1321. [Google Scholar] [CrossRef] [Green Version]
  46. Busbee, P.B.; Rouse, M.; Nagarkatti, M.; Nagarkatti, P.S. Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders. Nutr. Rev. 2013, 71, 353–369. [Google Scholar] [CrossRef] [Green Version]
  47. Rouse, M.; Nagarkatti, M.; Nagarkatti, P.S. The role of IL-2 in the activation and expansion of regulatory T-cells and the development of experimental autoimmune encephalomyelitis. Immunobiology 2013, 218, 674–682. [Google Scholar] [CrossRef] [Green Version]
  48. Singh, N.P.; Singh, U.P.; Rouse, M.; Zhang, J.; Chatterjee, S.; Nagarkatti, P.S.; Nagarkatti, M. Dietary indoles suppress delayed-type hypersensitivity by inducing a switch from proinflammatory Th17 cells to anti-inflammatory regulatory T cells through regulation of MicroRNA. J. Immunol. 2015, 196, 1108–1122. [Google Scholar] [CrossRef] [Green Version]
  49. Rothhammer, V.; Quintana, F.J. The aryl hydrocarbon receptor: An environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 2019, 19, 184–197. [Google Scholar] [CrossRef]
  50. Veldhoen, M.; Hirota, K.; Westendorf, A.M.; Buer, J.; Dumoutier, L.; Renauld, J.-C.; Stockinger, B. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nat. Cell Biol. 2008, 453, 106–109. [Google Scholar] [CrossRef]
  51. Chung, D.J.; Rossi, M.; Romano, E.; Ghith, J.; Yuan, J.; Munn, D.H.; Young, J.W. Indoleamine 2,3-dioxygenase–expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood 2009, 114, 555–563. [Google Scholar] [CrossRef]
  52. Baban, B.; Chandler, P.R.; Sharma, M.D.; Pihkala, J.; Koni, P.A.; Munn, D.H.; Mellor, A.L. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J. Immunol. 2009, 183, 2475–2483. [Google Scholar] [CrossRef] [Green Version]
  53. Sharma, M.D.; Hou, D.-Y.; Liu, Y.; Koni, P.A.; Metz, R.; Chandler, P.; Mellor, A.L.; He, Y.; Munn, D.H. Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 2009, 113, 6102–6111. [Google Scholar] [CrossRef] [Green Version]
  54. Nguyen, N.T.; Kimura, A.; Nakahama, T.; Chinen, I.; Masuda, K.; Nohara, K.; Fujii-Kuriyama, Y.; Kishimoto, T. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc. Natl. Acad. Sci. USA 2010, 107, 19961–19966. [Google Scholar] [CrossRef] [Green Version]
  55. Dietrich, C. Antioxidant functions of the aryl hydrocarbon receptor. Stem Cells Int. 2016, 2016, 1–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Furue, M.; Hashimoto-Hachiya, A.; Tsuji, G. Antioxidative phytochemicals accelerate epidermal terminal differentiation via the AHR-OVOL1 pathway: Implications for atopic dermatitis. Acta Derm. Venereol. 2018, 98, 918–923. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Furue, M.; Takahara, M.; Nakahara, T.; Uchi, H. Role of AhR/ARNT system in skin homeostasis. Arch. Dermatol. Res. 2014, 306, 769–779. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Kato, H.; Perl, A. Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4−CD8− double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus. J. Immunol. 2014, 192, 4134–4144. [Google Scholar] [CrossRef] [Green Version]
  59. Yang, J.; Yang, X.; Zou, H.; Li, M. Oxidative stress and treg and Th17 dysfunction in systemic lupus erythematosus. Oxidative Med. Cell. Longev. 2016, 2016, 1–9. [Google Scholar] [CrossRef]
  60. Kelepouri, D.; Mavropoulos, A.; Bogdanos, D.P.; Sakkas, L.I. The role of flavonoids in inhibiting Th17 responses in inflammatory arthritis. J. Immunol. Res. 2018, 2018, 1–11. [Google Scholar] [CrossRef]
  61. Wong, C.P.; Nguyen, L.P.; Noh, S.K.; Bray, T.M.; Bruno, R.S.; Ho, E. Induction of regulatory T cells by green tea polyphenol EGCG. Immunol. Lett. 2011, 139, 7–13. [Google Scholar] [CrossRef] [Green Version]
  62. Rathod, S.B.; Tripathy, A.S. TGF-β1 and contact mediated suppression by CD4+CD25+CD127− T regulatory cells of patients with self-limiting hepatitis E. Hum. Immunol. 2016, 77, 1254–1263. [Google Scholar] [CrossRef] [PubMed]
  63. Veldhoen, M.; Hocking, R.J.; Atkins, C.J.; Locksley, R.M.; Stockinger, B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006, 24, 179–189. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. You, P.; Chen, N.; Su, L.; Peng, T.; Chen, G.; Liu, Y. Local level of TGF-β1 determines the effectiveness of dexamethasone through regulating the balance of Treg/Th17 cells in TNBS-induced mouse colitis. Exp. Ther. Med. 2018, 15, 3639–3649. [Google Scholar] [CrossRef] [PubMed]
  65. Elyaman, W.; Bradshaw, E.M.; Uyttenhove, C.; Dardalhon, V.; Awasthi, A.; Imitola, J.; Bettelli, E.; Oukka, M.; Van Snick, J.; Renauld, J.-C.; et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc. Natl. Acad. Sci. USA 2009, 106, 12885–12890. [Google Scholar] [CrossRef] [Green Version]
  66. Hagenstein, J.; Melderis, S.; Nosko, A.; Warkotsch, M.T.; Richter, J.V.; Ramcke, T.; Herrnstadt, G.R.; Scheller, J.; Yan, I.; Mittrücker, H.-W.; et al. A Novel Role for IL-6 Receptor Classic Signaling: Induction of RORγt+Foxp3+ Tregs with Enhanced Suppressive Capacity. J. Am. Soc. Nephrol. 2019, 30, 1439–1453. [Google Scholar] [CrossRef] [PubMed]
  67. Khoshmirsafa, M.; Seif, F.; Bagheri, N.; Beshkar, P.; Mousavi, M.; Shirzad, H. Correlation of interleukin 6 and transforming growth factor β1 with peripheral blood regulatory T cells in rheumatoid arthritis patients: A potential biomarker. Central Eur. J. Immunol. 2018, 43, 281–288. [Google Scholar] [CrossRef]
  68. Tanaka, T. Can IL-6 blockade rectify imbalance between Tregs and Th17 cells? Immunotherapy 2013, 5, 695–697. [Google Scholar] [CrossRef]
  69. Liu, X.; Hu, H.; Fan, H.; Zuo, D.; Shou, Z.; Liao, Y.; Nan, Z.; Tang, Q. The role of STAT3 and AhR in the differentiation of CD4+ T cells into Th17 and Treg cells. Medicine 2017, 96, e6615. [Google Scholar] [CrossRef]
  70. Ehrlich, A.K.; Pennington, J.M.; Bisson, W.H.; Kolluri, S.K.; Kerkvliet, N.I. TCDD, FICZ, and other high affinity ahr ligands dose-dependently determine the fate of CD4+ T cell differentiation. Toxicol. Sci. 2017, 161, 310–320. [Google Scholar] [CrossRef] [Green Version]
  71. Al-Ghezi, Z.Z.; Singh, N.; Mehrpouya-Bahrami, P.; Busbee, P.B.; Nagarkatti, M.; Nagarkatti, P.S. AhR activation by TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin) attenuates pertussis toxin-induced inflammatory responses by differential regulation of tregs and Th17 cells through specific targeting by microRNA. Front. Microbiol. 2019, 10, 2349. [Google Scholar] [CrossRef] [PubMed]
  72. Busbee, P.B.; Menzel, L.; Alrafas, H.R.; Dopkins, N.; Becker, W.; Miranda, K.; Tang, C.; Chatterjee, S.; Singh, U.P.; Nagarkatti, M.; et al. Indole-3-carbinol prevents colitis and associated microbial dysbiosis in an IL-22–dependent manner. JCI Insight 2020, 5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Gagliani, N.; Vesely, M.C.A.; Iseppon, A.; Brockmann, L.; Xu, H.; Palm, N.W.; De Zoete, M.R.; Licona-Limón, P.; Paiva, R.S.; Ching, T.; et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nat. Cell Biol. 2015, 523, 221–225. [Google Scholar] [CrossRef] [PubMed]
  74. Mohinta, S.; Kannan, A.K.; Gowda, K.; Amin, S.G.; Perdew, G.H.; August, A. Differential regulation of th17 and t regulatory cell differentiation by aryl hydrocarbon receptor dependent xenobiotic response element dependent and independent pathways. Toxicol. Sci. 2015, 145, 233–243. [Google Scholar] [CrossRef] [Green Version]
  75. Liu, C.; Xia, M.; Zhang, Y.; Jin, P.; Zhao, L.; Zhang, J.; Li, T.; Zhou, X.; Tu, Y.; Kong, F.; et al. Micro124-mediated AHR expression regulates the inflammatory response of chronic rhinosinusitis (CRS) with nasal polyps. Biochem. Biophys. Res. Commun. 2018, 500, 145–151. [Google Scholar] [CrossRef] [PubMed]
  76. Neamah, W.H.; Singh, N.P.; Alghetaa, H.; Abdulla, O.A.; Chatterjee, S.; Busbee, P.B.; Nagarkatti, M.; Nagarkatti, P.S. AhR Activation Leads to Massive Mobilization of Myeloid-Derived Suppressor Cells with Immunosuppressive Activity through Regulation of CXCR2 and MicroRNA miR-150-5p and miR-543-3p That Target Anti-Inflammatory Genes. J. Immunol. 2019, 203, 1830–1844. [Google Scholar] [CrossRef]
  77. Serafini, P.; Mgebroff, S.; Noonan, K.; Borrello, I. Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res. 2008, 68, 5439–5449. [Google Scholar] [CrossRef] [Green Version]
  78. Lv, Q.; Shi, C.; Qiao, S.; Cao, N.; Guan, C.; Dai, Y.; Wei, Z. Alpinetin exerts anti-colitis efficacy by activating AhR, regulating miR-302/DNMT-1/CREB signals, and therefore promoting Treg differentiation. Cell Death Dis. 2018, 9, 1–25. [Google Scholar] [CrossRef]
  79. Chinen, I.; Nakahama, T.; Kimura, A.; Nguyen, N.T.; Takemori, H.; Kumagai, A.; Kayama, H.; Takeda, K.; Lee, S.; Hanieh, H.; et al. The aryl hydrocarbon receptor/microRNA-212/132 axis in T cells regulates IL-10 production to maintain intestinal homeostasis. Int. Immunol. 2015, 27, 405–415. [Google Scholar] [CrossRef]
  80. Nakahama, T.; Hanieh, H.; Nguyen, N.T.; Chinen, I.; Ripley, B.; Millrine, D.; Lee, S.; Nyati, K.K.; Dubey, P.K.; Chowdhury, K.; et al. Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17-producing T-helper cell differentiation. Proc. Natl. Acad. Sci. USA 2013, 110, 11964–11969. [Google Scholar] [CrossRef] [Green Version]
  81. Busbee, P.B.; Nagarkatti, M.; Nagarkatti, P. Natural Indoles, Indole-3-Carbinol (I3C) and 3,3′-Diindolylmethane (DIM), Attenuate Staphylococcal Enterotoxin B-Mediated Liver Injury by Downregulating miR-31 Expression and Promoting Caspase-2-Mediated Apoptosis. PLoS ONE 2015, 10, e0118506. [Google Scholar] [CrossRef]
  82. Busbee, P.B.; Nagarkatti, M.; Nagarkatti, P.S. Natural indoles, indole-3-carbinol and 3,3′-diindolymethane, inhibit T cell activation by staphylococcal enterotoxin B through epigenetic regulation involving HDAC expression. Toxicol. Appl. Pharmacol. 2014, 274, 7–16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Singh, N.P.; Hegde, V.L.; Hofseth, L.J.; Nagarkatti, M.; Nagarkatti, P. Resveratrol (trans-3,5,4′-Trihydroxystilbene) Ameliorates Experimental Allergic Encephalomyelitis, Primarily via Induction of Apoptosis in T Cells Involving Activation of Aryl Hydrocarbon Receptor and Estrogen Receptor. Mol. Pharmacol. 2007, 72, 1508–1521. [Google Scholar] [CrossRef] [Green Version]
  84. Singh, U.P.; Singh, N.P.; Singh, B.; Hofseth, L.J.; Price, R.L.; Nagarkatti, M.; Nagarkatti, P.S. Resveratrol (trans-3,5,4′-trihydroxystilbene) induces silent mating type information regulation-1 and down-regulates nuclear transcription factor-kappaB activation to abrogate dextran sulfate sodium-induced colitis. J. Pharmacol. Exp. Ther. 2009, 332, 829–839. [Google Scholar] [CrossRef] [Green Version]
  85. Metidji, A.; Omenetti, S.; Crotta, S.; Li, Y.; Nye, E.; Ross, E.; Li, V.; Maradana, M.R.; Schiering, C.; Stockinger, B. The environmental sensor ahr protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 2018, 49, 353–362.e5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Zelante, T.; Iannitti, R.G.; Cunha, C.; De Luca, A.; Giovannini, G.; Pieraccini, G.; Zecchi, R.; D’Angelo, C.; Massi-Benedetti, C.; Fallarino, F.; et al. Tryptophan Catabolites from Microbiota Engage Aryl Hydrocarbon Receptor and Balance Mucosal Reactivity via Interleukin-22. Immuniity 2013, 39, 372–385. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Kwon, T.H.; Yoon, I.H.; Shin, J.-S.; Lee, Y.H.; Kwon, B.J.; Lee, K.-T.; Lee, Y.S. Synthesis of indolyl-3-acetonitrile derivatives and their inhibitory effects on nitric oxide and PGE2 productions in LPS-induced RAW 264.7 cells. Bioorganic Med. Chem. Lett. 2013, 23, 2571–2574. [Google Scholar] [CrossRef]
  88. Quintana, F.J.; Murugaiyan, G.; Farez, M.F.; Mitsdoerffer, M.; Tukpah, A.-M.; Burns, E.J.; Weiner, H.L. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 2010, 107, 20768–20773. [Google Scholar] [CrossRef] [Green Version]
  89. Chang, Y.-C.; Riby, J.; Chang, G.H.-F.; Peng, B.; Firestone, G.; Bjeldanes, L.F. Cytostatic and antiestrogenic effects of 2-(indol-3-ylmethyl)-3,3′-diindolylmethane, a major in vivo product of dietary indole-3-carbinol. Biochem. Pharmacol. 1999, 58, 825–834. [Google Scholar] [CrossRef]
  90. Su, M.; Qian, C.; Hu, Y.; Lu, W.; Huang, R.; Chen, M.; Chen, J. Inhibitory effect of the low-toxic exogenous aryl hydrocarbon receptor modulator 3′3-diindolylmethane on gastric cancer in mice. Oncol. Lett. 2017, 14, 8100–8105. [Google Scholar] [CrossRef] [Green Version]
  91. Ji, Y.; Yin, W.; Liang, Y.; Sun, L.; Yin, Y.; Zhang, W. Anti-Inflammatory and Anti-Oxidative Activity of Indole-3-Acetic Acid Involves Induction of HO-1 and Neutralization of Free Radicals in RAW264.7 Cells. Int. J. Mol. Sci. 2020, 21, 1579. [Google Scholar] [CrossRef] [Green Version]
  92. Kim, D.; Kim, H.; Kim, K.; Roh, S. The protective effect of indole-3-acetic acid (IAA) on H2O2-damaged human dental pulp stem cells is mediated by the AKT pathway and involves increased expression of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and its downstream target heme oxygenase 1 (HO-1). Oxidative Med. Cell. Longev. 2017, 2017, 1–11. [Google Scholar] [CrossRef]
  93. Borghi, M.; Pariano, M.; Solito, V.; Puccetti, M.; Bellet, M.M.; Stincardini, C.; Renga, G.; Vacca, C.; Sellitto, F.; Mosci, P.; et al. Targeting the aryl hydrocarbon receptor with indole-3-aldehyde protects from vulvovaginal candidiasis via the IL-22-IL-18 cross-talk. Front. Immunol. 2019, 10. [Google Scholar] [CrossRef]
  94. Quintana, F.J.; Sherr, D.H. Aryl Hydrocarbon Receptor Control of Adaptive Immunity. Pharmacol. Rev. 2013, 65, 1148–1161. [Google Scholar] [CrossRef] [Green Version]
  95. Abdellatif, K.R.A.; Lamie, P.F.; Omar, H.A. 3-Methyl-2-phenyl-1-substituted-indole derivatives as indomethacin analogs: Design, synthesis and biological evaluation as potential anti-inflammatory and analgesic agents. J. Enzym. Inhib. Med. Chem. 2015, 31, 318–324. [Google Scholar] [CrossRef]
  96. Gutiérrez-Vázquez, C.; Quintana, F.J. Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity 2018, 48, 19–33. [Google Scholar] [CrossRef] [Green Version]
  97. Lin, Y.-H.; Luck, H.; Khan, S.; Schneeberger, P.H.H.; Tsai, S.; Clemente-Casares, X.; Lei, H.; Leu, Y.-L.; Chan, Y.T.; Chen, H.-Y.; et al. Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity. Int. J. Obes. 2019, 43, 2407–2421. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Lin, Y.-K.; Leu, Y.-L.; Huang, T.-H.; Wu, Y.-H.; Chung, P.-J.; Pang, J.-H.S.; Hwang, T.-L. Anti-inflammatory effects of the extract of indigo naturalis in human neutrophils. J. Ethnopharmacol. 2009, 125, 51–58. [Google Scholar] [CrossRef] [PubMed]
  99. Zhang, A.; Ning, B.; Sun, N.; Wei, J.; Ju, X. Indirubin increases CD4+CD25+Foxp3+ regulatory T cells to prevent immune thrombocytopenia in mice. PLoS ONE 2015, 10, e0142634. [Google Scholar] [CrossRef] [PubMed]
  100. Hung, S.-C.; Kuo, K.-L.; Huang, H.-L.; Lin, C.-C.; Tsai, T.-H.; Wang, C.-H.; Chen, J.-W.; Lin, S.-J.; Huang, P.-H.; Tarng, D.-C. Indoxyl sulfate suppresses endothelial progenitor cell–mediated neovascularization. Kidney Int. 2016, 89, 574–585. [Google Scholar] [CrossRef] [Green Version]
  101. Kim, H.Y.; Yoo, T.-H.; Hwang, Y.; Lee, G.H.; Kim, B.; Jang, J.; Yu, H.T.; Kim, M.C.; Cho, J.-Y.; Lee, C.J.; et al. Indoxyl sulfate (IS)-mediated immune dysfunction provokes endothelial damage in patients with end-stage renal disease (ESRD). Sci. Rep. 2017, 7, 1–16. [Google Scholar] [CrossRef] [Green Version]
  102. Schroeder, J.C.; DiNatale, B.C.; Murray, I.A.; Flaveny, C.A.; Liu, Q.; Laurenzana, E.M.; Lin, J.M.; Strom, S.C.; Omiecinski, C.J.; Amin, S.; et al. The Uremic Toxin 3-Indoxyl Sulfate Is a Potent Endogenous Agonist for the Human Aryl Hydrocarbon Receptor. Biochemistry 2010, 49, 393–400. [Google Scholar] [CrossRef] [Green Version]
  103. Mezrich, J.D.; Fechner, J.H.; Zhang, X.; Johnson, B.P.; Burlingham, W.J.; Bradfield, C.A. An Interaction between Kynurenine and the Aryl Hydrocarbon Receptor Can Generate Regulatory T Cells. J. Immunol. 2010, 185, 3190–3198. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Fazio, F.; Lionetto, L.; Molinaro, G.; Bertrand, H.O.; Acher, F.; Ngomba, R.T.; Notartomaso, S.; Curini, M.; Rosati, O.; Scarselli, P.; et al. Cinnabarinic Acid, an Endogenous Metabolite of the Kynurenine Pathway, Activates Type 4 Metabotropic Glutamate Receptors. Mol. Pharmacol. 2012, 81, 643–656. [Google Scholar] [CrossRef] [Green Version]
  105. Fazio, F.; Zappulla, C.; Notartomaso, S.; Busceti, C.L.; Bessede, A.; Scarselli, P.; Vacca, C.; Gargaro, M.; Volpi, C.; Allegrucci, M.; et al. Cinnabarinic acid, an endogenous agonist of type-4 metabotropic glutamate receptor, suppresses experimental autoimmune encephalomyelitis in mice. Neuropharmacology 2014, 81, 237–243. [Google Scholar] [CrossRef]
Ijms 21 07849 g001 550
Figure 1. Signaling pathways that lead to the generation of Tregs versus Th17 cells following activation of AhR by a variety of ligands.
Figure 1. Signaling pathways that lead to the generation of Tregs versus Th17 cells following activation of AhR by a variety of ligands.
Ijms 21 07849 g001
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Prasad Singh, N.; Nagarkatti, M.; Nagarkatti, P. From Suppressor T Cells to Regulatory T Cells: How the Journey that Began with the Discovery of the Toxic Effects of TCDD Led to Better Understanding of the Role of AhR in Immunoregulation. Int. J. Mol. Sci. 2020, 21, 7849. https://doi.org/10.3390/ijms21217849

AMA Style

Prasad Singh N, Nagarkatti M, Nagarkatti P. From Suppressor T Cells to Regulatory T Cells: How the Journey that Began with the Discovery of the Toxic Effects of TCDD Led to Better Understanding of the Role of AhR in Immunoregulation. International Journal of Molecular Sciences. 2020; 21(21):7849. https://doi.org/10.3390/ijms21217849

Chicago/Turabian Style

Prasad Singh, Narendra, Mitzi Nagarkatti, and Prakash Nagarkatti. 2020. "From Suppressor T Cells to Regulatory T Cells: How the Journey that Began with the Discovery of the Toxic Effects of TCDD Led to Better Understanding of the Role of AhR in Immunoregulation" International Journal of Molecular Sciences 21, no. 21: 7849. https://doi.org/10.3390/ijms21217849

APA Style

Prasad Singh, N., Nagarkatti, M., & Nagarkatti, P. (2020). From Suppressor T Cells to Regulatory T Cells: How the Journey that Began with the Discovery of the Toxic Effects of TCDD Led to Better Understanding of the Role of AhR in Immunoregulation. International Journal of Molecular Sciences, 21(21), 7849. https://doi.org/10.3390/ijms21217849

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop