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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Immunol.</journal-id>
<journal-title>Frontiers in Immunology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Immunol.</abbrev-journal-title>
<issn pub-type="epub">1664-3224</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fimmu.2022.951339</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Immunology</subject>
<subj-group>
<subject>Mini Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Reciprocal Interactions Between Regulatory T Cells and Intestinal Epithelial Cells</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Jiang</surname>
<given-names>Zhiqiang</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1244772"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Wu</surname>
<given-names>Chuan</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1064796"/>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Sun-Yat Sen University, School of Medicine</institution>, <addr-line>Guangzhou</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Experimental Immunology Branch, National Cancer Institute, National Institute of Health (NIH)</institution>, <addr-line>Bethesda, MD</addr-line>, <country>United States</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Xuyu Zhou, Chinese Academy of Sciences (CAS), China</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Ye Zheng, Salk Institute for Biological Studies, United States</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Zhiqiang Jiang, <email xlink:href="mailto:Jiangzhq5@mail.sysu.edu.cn">Jiangzhq5@mail.sysu.edu.cn</email>; Chuan Wu, <email xlink:href="mailto:chuan.wu@nih.gov">chuan.wu@nih.gov</email>
</p>
</fn>
<fn fn-type="other" id="fn002">
<p>This article was submitted to T Cell Biology, a section of the journal Frontiers in Immunology</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>04</day>
<month>07</month>
<year>2022</year>
</pub-date>
<pub-date pub-type="collection">
<year>2022</year>
</pub-date>
<volume>13</volume>
<elocation-id>951339</elocation-id>
<history>
<date date-type="received">
<day>23</day>
<month>05</month>
<year>2022</year>
</date>
<date date-type="accepted">
<day>09</day>
<month>06</month>
<year>2022</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2022 Jiang and Wu</copyright-statement>
<copyright-year>2022</copyright-year>
<copyright-holder>Jiang and Wu</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>It has been well established that Foxp3+ regulatory T cells (Treg cells) play a crucial role for immune repression and tolerance, protecting the body from autoimmunity and inflammation. Previous studies indicate that intestinal Treg cells are one specialized population of Treg cells, distinct from those in other organ compartments, both functionally and phenotypically. Specific external and internal signals, particularly the presence of microbiota, shape these Treg cells to better cooperate with the gut ecosystem, controlling intestinal physiology. The integrity of intestinal epithelial barrier represents a key feature of gut immune tolerance, which can be regulated by multiple factors. Emerging evidence suggests that bidirectional interactions between gut epithelium and resident T cells significantly contribute to intestinal barrier function. Understanding how Treg cells regulate intestinal barrier integrity provides insights into immune tolerance-mediated mucosal homeostasis, which can further illuminate potential therapeutic strategies for treating inflammatory bowel disease and colon cancer.</p>
</abstract>
<kwd-group>
<kwd>regulatory (treg) cell</kwd>
<kwd>intestinal epithelia cell</kwd>
<kwd>intestinal barrier</kwd>
<kwd>microbiota</kwd>
<kwd>dietary antigen</kwd>
</kwd-group>
<counts>
<fig-count count="0"/>
<table-count count="0"/>
<equation-count count="0"/>
<ref-count count="96"/>
<page-count count="7"/>
<word-count count="2729"/>
</counts>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<title>Introduction</title>
<p>Regulatory T cells (Treg cells) are a specialized T cell subset which play a critical role in controlling immune homeostasis and peripheral tolerance (<xref ref-type="bibr" rid="B1">1</xref>, <xref ref-type="bibr" rid="B2">2</xref>). Intestinal Treg cells mainly develop and differentiate in the thymus as thymic Treg (tTreg) cells, or can be induced in the periphery as peripheral Treg (pTreg) cells (<xref ref-type="bibr" rid="B3">3</xref>, <xref ref-type="bibr" rid="B4">4</xref>). tTreg cells are generated after self-antigen recognition by T cell receptor in the thymus while pTreg cells are derived by non-self-antigen from na&#xef;ve T cells. While these two types of Treg cells show complementary functions and different genetic signatures, they both express master transcription factor Foxp3 (<xref ref-type="bibr" rid="B5">5</xref>, <xref ref-type="bibr" rid="B6">6</xref>). The function of Foxp3<sup>+</sup> Treg cells for gut physiology has been documented in patients with immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome who lost the Treg cells (<xref ref-type="bibr" rid="B7">7</xref>). These patients exhibit symptoms of spontaneous inflammation in multiple organs, with most severe disorders on the mucosal surfaces, including the gastrointestinal (GI) tract (<xref ref-type="bibr" rid="B8">8</xref>). Plus, Foxp3 deficient mice (Scurfy) as well display severe autoimmunity in the gut (<xref ref-type="bibr" rid="B5">5</xref>, <xref ref-type="bibr" rid="B9">9</xref>). These findings indicate that Treg cells are crucial for the intestinal immune tolerance. Considering the distinct antigen repertoires, intestinal pTreg cells are mainly responsible for immune tolerance against environmental insults, whereas tTreg cells protect the tissue from autoreactive responses.</p>
<p>The intestinal epithelium represents the largest interface which protects the body from potential danger while sensing external milieu. The monolayer of intestinal epithelial cells (IECs) form a physical barrier to segregate external environment from the intestinal tissues. Given the constant challenges and insults from dietary and microbial antigens, the integrity of intestinal epithelium barrier is a key feature of gut homeostasis (<xref ref-type="bibr" rid="B10">10</xref>). In addition to immune suppression, newly emerging evidence suggests that intestinal Treg cells also exert function for epithelium tissue repair and mucosal barrier maintenance (<xref ref-type="bibr" rid="B11">11</xref>). Hence, to elucidate how Treg-IEC crosstalk participates in gut physiology and pathophysiology is essential for the comprehension of tissue adaptation of Treg cells in the intestinal microenvironment.</p>
<p>In this Review, we will summarize and discuss the current understanding of how mutualism between Treg cells and IECs contribute to GI physiology and immune tolerance.</p>
</sec>
<sec id="s2">
<title>Gut Treg Subsets</title>
<p>In general, tTreg cells infiltrating in lamina propria (LP) inductive site origin from those tTreg cells propagating in peripheral blood, while pTreg cells accumulating in LP inductive site are mainly comprised by locally differentiated na&#xef;ve T cells (<xref ref-type="bibr" rid="B12">12</xref>). The surface homing molecules CCR7 and CD62L direct tTreg and na&#xef;ve T cells migrate into gut-associated lymphoid tissue (GALT) or gut-draining mesenteric lymph nodes (mLN). In these lymphoid compartments, tTreg cells expand when expose to unknown signals (<xref ref-type="bibr" rid="B13">13</xref>) and a substantial proportion of the na&#xef;ve T cells differentiate into pTreg cells. Thereafter tTreg and pTreg cells migrate into LP effective site facilitated by &#x3b1;4&#x3b2;7 integrin and CCR9 signaling (<xref ref-type="bibr" rid="B14">14</xref>, <xref ref-type="bibr" rid="B15">15</xref>). Unlike tTreg cells, pTreg cells expand inside of LP after exposed to commensal and dietary antigens (<xref ref-type="bibr" rid="B13">13</xref>). With an exception of the common pTreg homing route, there remain some pTreg cells found in LP, differentiated by TGF-&#x3b2; and retinoic acid (RA) producing eosinophils (<xref ref-type="bibr" rid="B16">16</xref>). In concert with freshly infiltrated tTreg and pTreg cells, there is also a subset of memory Treg cells resident in LP expand and exert immune suppression functions when induced in the gut. These CD103 expressing memory Treg cells are generated in a previous induction event and quiescent to exhibit tissue resident feature to join in the Treg pool to maintain mucosal homeostasis (<xref ref-type="bibr" rid="B17">17</xref>).</p>
<p>Although tTreg and pTreg cells are both able to exert immunosuppression function in the gut, they function independently and synergistically to maintain mucosal tolerance. tTreg cells and pTreg cells have different TCR repertoires, and thus response to different antigens. tTreg cells normally recognize self-antigen, and therefore response to those exposed antigens expressed by IECs, particularly under certain intestinal perturbations such as sterile injuries (<xref ref-type="bibr" rid="B18">18</xref>). pTreg cells normally recognize alien-antigens such as dietary metabolites and microbe-antigens and expand at the induction site (<xref ref-type="bibr" rid="B19">19</xref>, <xref ref-type="bibr" rid="B20">20</xref>). In addition, strong TCR affinity facilitates the generation of a small portion of cross-react Treg cells with not fully elucidated reasons (<xref ref-type="bibr" rid="B18">18</xref>), including self-antigen responding pTreg cells (<xref ref-type="bibr" rid="B21">21</xref>) and foreign antigen responding tTreg cells (<xref ref-type="bibr" rid="B22">22</xref>). The variety of TCR repertoires covered by tTreg cells and pTreg cells are both required in regulating intestinal immune responses. It has been shown that adoptive transfer of tTreg cells alone is not sufficient to fully rescue Foxp3 deficiency during murine model of colitis, unless Foxp3<sup>&#x2013;</sup>CD4<sup>+</sup> T cells are co-transferred, suggesting that both tTreg and pTreg cells are required for optimal protection during intestinal inflammation (<xref ref-type="bibr" rid="B23">23</xref>, <xref ref-type="bibr" rid="B24">24</xref>). These findings shed light on developing Treg transfer therapy for potential treatment of human IBD patients.</p>
</sec>
<sec id="s3">
<title>IEC-Mediated Intestinal Treg Cells Induction and Function</title>
<sec id="s3_1">
<title>IEC-Expressed MHC-II Independent Intestinal Treg Cells</title>
<p>Different studies have shown that intestinal Treg cells can be controlled <italic>via</italic> both IEC independent and dependent manners. Interaction between IEC and dendritic cell (DC) facilitates generation of tolerogenic DC <italic>via</italic> TGF-&#x3b2; and RA, which promotes intestinal Treg cells differentiation and restrains inflammation of colitis (<xref ref-type="bibr" rid="B25">25</xref>). Meanwhile, IECs are known to secret exosomes to the extracellular environment, which induce the tolerogenic properties to DCs for the generation of Treg cells in the gut (<xref ref-type="bibr" rid="B26">26</xref>). Additionally, other IEC-derived factors such as cytokines are as well known to modulate Treg cells differentiation and function. For instance, IEC-derived IL-18 modulates effector T cell differentiation in the gut which indirectly influence Treg function (<xref ref-type="bibr" rid="B27">27</xref>). Another study indicates that during intestinal tumorigenesis, IECs promotes specific subset of KLRG1<sup>+</sup>GATA3<sup>+</sup> Treg cells accumulation mediated <italic>via</italic> IL-33 (<xref ref-type="bibr" rid="B28">28</xref>).</p>
</sec>
<sec id="s3_2">
<title>IEC-Expressed MHC-II Dependent Intestinal Treg Cells</title>
<p>Complement to the DC studies, intestinal Treg cells can also be directly induced by MHC class II (MHC-II) on IECs. It has been shown that both human and mouse IECs express MHC-II molecules (<xref ref-type="bibr" rid="B29">29</xref>&#x2013;<xref ref-type="bibr" rid="B32">32</xref>). IECs single cell survey identifies the expression of MHC-II on IECs (<xref ref-type="bibr" rid="B33">33</xref>), suggesting that IECs function as non-conventional APCs (<xref ref-type="bibr" rid="B34">34</xref>). The induction of MHC-II on IECs has been demonstrated to be IFN-&#x3b3;&#x2212;dependent (<xref ref-type="bibr" rid="B35">35</xref>&#x2013;<xref ref-type="bibr" rid="B39">39</xref>). It has been reported that IEC-derived MHC-II is sufficient to induce effector CD4<sup>+</sup> T cells activation in GvHD model (<xref ref-type="bibr" rid="B37">37</xref>). Several studies have implicate that IECs preferentially promote suppressive Treg cell responses (<xref ref-type="bibr" rid="B38">38</xref>). Loss of MHC-II on IECs results in elevated levels of colitis associated with reduced Treg cells (<xref ref-type="bibr" rid="B34">34</xref>, <xref ref-type="bibr" rid="B38">38</xref>). The expression of antigens by IECs leads to the proliferation of antigen-specific Treg cells in the intestine, which is further shown to be MHC-II-dependent (<xref ref-type="bibr" rid="B40">40</xref>). Moreover, intestinal mononuclear phagocytes (MNPs) have been reported to acquire MHC-II from IECs, subsequently assisting the generation of Treg cells (<xref ref-type="bibr" rid="B41">41</xref>). However, contradictory data show that MHC-II molecules are dispensable for T cell activation during murine colitis (<xref ref-type="bibr" rid="B42">42</xref>), raising the possibility that IEC-mediated T cell activation is context-dependent. Additional to IEC-mediated Treg cell expansion, recent study demonstrates that intestinal Treg cells are converted into CD4<sup>+</sup>Foxp3<sup>&#x2013;</sup> IELs to control intestinal inflammation, indicating the critical role of IECs in controlling environmental adaptation of Treg cells in the gut (<xref ref-type="bibr" rid="B43">43</xref>). IECs from small intestine also provide a unique IL-2 independent milieu for the maintenance and survival of Treg cells (<xref ref-type="bibr" rid="B44">44</xref>). Altogether, the microenvironment of epithelium calibrates cellular and functional properties of Treg cells to cope with dynamic change in the gut.</p>
</sec>
</sec>
<sec id="s4">
<title>Microbiota-Derived Intestinal Treg Cells</title>
<p>IECs are critical for microbial-mediated T cell differentiation and accumulation. It has been long established that segmented filamentous bacteria (SFB) promote intestinal Th17 cell differentiation which requires the direct adhesion of SFB on epithelium (<xref ref-type="bibr" rid="B45">45</xref>&#x2013;<xref ref-type="bibr" rid="B47">47</xref>). The SFB-IEC interaction leads to the production of serum amyloid A (SAA) from IECs which is critical for Th17 cell differentiation (<xref ref-type="bibr" rid="B48">48</xref>). Loss of such interaction compromises the induction of Th17 cells, indicating IEC plays a role of a key mediator in T cell responses to microbes (<xref ref-type="bibr" rid="B48">48</xref>). Similarly, gut Treg cells have also been shown to be induced from na&#xef;ve T cells by antigens derived from commensal bacteria, which are known as inducible Treg cells (<xref ref-type="bibr" rid="B49">49</xref>). It has been reported that commensal bacteria such as Clostridium species and <italic>B. fragilis</italic> are able to induce peripheral Treg cells <italic>via</italic> IEC dependent or independent manners (<xref ref-type="bibr" rid="B50">50</xref>, <xref ref-type="bibr" rid="B51">51</xref>). The Clostridia colonize the mucus layer without direct adhesion to IECs. The colonization of Clostridium species is found to impact on IECs for the production of TGF-&#x3b2; and indoleamine 2,3-dioxygenase (IDO), which could contribute to the induction of colonic Treg cells (<xref ref-type="bibr" rid="B52">52</xref>, <xref ref-type="bibr" rid="B53">53</xref>). More importantly, <italic>de novo</italic> generation of intestinal Treg cells may require synergistic effects with different Clostridia species, given the fact that a single species is insufficient in polarizing Treg cells (<xref ref-type="bibr" rid="B54">54</xref>). Additional to TGF-&#x3b2; and IDO-derived from IECs, Clostridia may also induce Treg cell generation <italic>via</italic> producing short chain fatty acids (SCFAs) by diffusing through the epithelium to LP (<xref ref-type="bibr" rid="B55">55</xref>&#x2013;<xref ref-type="bibr" rid="B58">58</xref>). Moreover, gut bacteria also generate secondary bile acids which can modulate the balance of Th17 and pTreg cells for intestinal immune homeostasis. (<xref ref-type="bibr" rid="B59">59</xref>). While Clostridia species are known to regulate Treg cells <italic>via</italic> IEC dependent manners, other microbiota species including <italic>Lactobacilli</italic> and <italic>Bifidobacteria</italic>, can also induce and activate colonic Treg cells by IEC independent manners (<xref ref-type="bibr" rid="B50">50</xref>, <xref ref-type="bibr" rid="B60">60</xref>&#x2013;<xref ref-type="bibr" rid="B62">62</xref>). It is now commonly recognized that microbiota modulates T cell differentiation and function in the gut for intestinal physiology (<xref ref-type="bibr" rid="B63">63</xref>). Given that Clostridia and Bacteroides species are two prominent members of the mammalian gut microbiota, such microbiota-mediated Treg cell regulation could be one machinery for the maintenance of gut homeostasis. Recent study further elucidates that mucosa-associated fungi also modulates gut Th17 responses for intestinal barrier function (<xref ref-type="bibr" rid="B64">64</xref>). Specifically, both <italic>Candida albicans</italic> and <italic>Staphylococcus aureus</italic> are identified to be strong inducers of human Th17 responses (<xref ref-type="bibr" rid="B65">65</xref>, <xref ref-type="bibr" rid="B66">66</xref>). These findings implicate that T cell differentiation and function could be regulated by a diverse community of bacteria, viruses, protozoa, and fungi within the GI tract (<xref ref-type="bibr" rid="B67">67</xref>). Given close proximity of gut microbiota and epithelium barrier, IECs play a critical role in bridging the crosstalk between different microbes and hosts for immune regulation in the gut. The precise mechanisms of how IECs collaborate with different microbial for immune tolerance is still under investigation, including Treg cells generation and function.</p>
</sec>
<sec id="s5">
<title>Diet-Derived Intestinal Treg Cells</title>
<p>Dietary components largely influence the development and function of intestinal Treg cells, which can be mediated by IEC-dependent and -independent manners. Dietary antigens are known to directly induce ROR&#x3b3;t<sup>+</sup> pTreg cells which are essential for the induction of oral tolerance (<xref ref-type="bibr" rid="B19">19</xref>, <xref ref-type="bibr" rid="B68">68</xref>). Dietary vitamin A-derived retinoic acid regulates the differentiation and accumulation of Treg cells, which exerts both pro- and anti-inflammatory functions (<xref ref-type="bibr" rid="B69">69</xref>, <xref ref-type="bibr" rid="B70">70</xref>). The metabolite of vitamin D3, 1,25-dihyroxyvitamin D3 can promote Treg cell differentiation (<xref ref-type="bibr" rid="B71">71</xref>). Interaction between vitamin B9 and its receptor (folic acid receptor 4) on Treg cells facilitates colonic Treg cell survival (<xref ref-type="bibr" rid="B72">72</xref>), protecting the mice from colitis (<xref ref-type="bibr" rid="B73">73</xref>). Additionally, vitamin C transporter was found to highly expressed on Treg cells. Vitamin C treatment leads to impaired suppressive function of tTreg cells, whereas it promotes pTreg cell generation both <italic>in vitro</italic> and <italic>in vivo</italic> (<xref ref-type="bibr" rid="B74">74</xref>). High salt diet (HSD) has also been reported to promote pathogenic Th17 responses <italic>via</italic> SGK1-Foxo1 signaling pathway while dampening Treg cell function, enhancing the susceptibility of autoimmunity and inflammation (<xref ref-type="bibr" rid="B75">75</xref>&#x2013;<xref ref-type="bibr" rid="B78">78</xref>). Moreover, it has been suggested that HSD modulates gut microbial responses for proinflammatory T cells generation in human (<xref ref-type="bibr" rid="B79">79</xref>). And clinical study shows that dietary sodium intake positively correlates with the severity of autoimmunity (<xref ref-type="bibr" rid="B80">80</xref>). Further, another study demonstrates that dietary-derived sugar, D-mannose, induces Treg cell generation in both human and mouse cells by promoting TGF-&#x3b2; activation. Supplement of D-mannose represses proinflammatory responses in animal models of autoimmunity (<xref ref-type="bibr" rid="B81">81</xref>). Moreover, dietary fibers can be fermented and converted into SCFAs through gut microbiota. Various studies suggest that SCFAs stimulate Treg cell differentiation, expansion and accumulation through activation of different G protein-coupled receptors such as GPR43 (<xref ref-type="bibr" rid="B58">58</xref>), GPR109A (<xref ref-type="bibr" rid="B82">82</xref>) and GPR15 (<xref ref-type="bibr" rid="B83">83</xref>). Tryptophan is another critical food component as an essential amino acid. It can be metabolized to kynurenin through IECs which modulates Treg cell development (<xref ref-type="bibr" rid="B84">84</xref>). Tryptophan is also the precursor of vitamin B3. Vitamin B3 binds to its receptor GPR109A on macrophages and DCs in the gut, leading to differentiation of Treg cells. Loss of GPR109A results in elevated levels of intestinal inflammation (<xref ref-type="bibr" rid="B82">82</xref>). Collectively, these pieces of data indicate that both dietary components modulate Treg cell generation and function in the gut, providing insight of dietary-based therapies in controlling intestinal inflammation.</p>
</sec>
<sec id="s6">
<title>Treg Cells Modulate Intestinal Epithelium Barrier Functions</title>
<p>Foxp3<sup>+</sup> Treg cells play a critical role in regulating IEC homeostasis and intestinal barrier integrity. Although various of cellular sources contribute to intestinal IL-10, as one major effector molecule from Treg cells, Treg cell-derived IL-10 has been demonstrated to play a key role for the maintenance of mucosal immune homeostasis (<xref ref-type="bibr" rid="B85">85</xref>, <xref ref-type="bibr" rid="B86">86</xref>). Recent study indicates that Treg cells are required for intestinal stem cells (ISC) renewal <italic>via</italic> IL-10. Loss of Treg cells results in decreased ISC frequency with elevated levels of IEC differentiation (<xref ref-type="bibr" rid="B35">35</xref>). T cell-derived IL-10 has been reported to regulate the IECs function <italic>via</italic> inhibiting their fucosylation (<xref ref-type="bibr" rid="B87">87</xref>). Further, IL-10 is demonstrated to suppress Fas-mediated IEC apoptosis (<xref ref-type="bibr" rid="B88">88</xref>), and protects IEC from endoplasmic reticulum stress for epithelium barrier integrity (<xref ref-type="bibr" rid="B89">89</xref>, <xref ref-type="bibr" rid="B90">90</xref>). Given the immune regulatory function of Treg cells in the gut, they are thus able to control epithelium barrier function indirectly by impacting other immune cells. For instance, it is known that Treg cells control the abundance of Th17 cells in the gut. And intestinal Th17 cells-derived cytokines such as IL-17 and IL-22, are beneficial for mucosal barrier function (<xref ref-type="bibr" rid="B91">91</xref>&#x2013;<xref ref-type="bibr" rid="B93">93</xref>). Moreover, a previous study indicated that Treg cells improve intestinal barrier function by regulating neutrophil infiltration during heatstroke (<xref ref-type="bibr" rid="B94">94</xref>). Treg cells have also been shown to enhance intestinal barrier function by repressing type 2 responses during food allergy (<xref ref-type="bibr" rid="B95">95</xref>). The process of generating pTreg cells from na&#xef;ve T cells carrying environmental antigen specific TCRs is important since it can prevent these T cells from eliciting harmful immune responses. pTreg cell deficient mice exhibit spontaneous inflammation in the GI tract associated with altered microbiota (<xref ref-type="bibr" rid="B96">96</xref>). Hence, the reciprocal interactions between IEC and Treg cells are delicately balanced by the gut microenvironment while controlling intestinal barrier physiology.</p>
</sec>
<sec id="s7" sec-type="conclusions">
<title>Conclusions</title>
<p>Intestinal Treg cells are critical for establishing gut tolerance and host defense. The heterogenicity of these Treg cells are beneficial for protecting the intestinal tissue from various sources of insults. Importantly, the IECs play a key role in connecting environmental cues to tissue immune system for the induction, expansion and function of Treg cells. While the role of IEC as non-canonical APC has been studied, further investigation is still required to illustrate the molecular mechanism of IEC-Treg cell crosstalk. These include correlation of spatial expression pattern of MHC-II on IECs with Treg cell distribution, intracellular signaling pathways of antigen process and presentation by IECs and how specific mediators produced by IECs mediate Treg cells generation and function. Moreover, because of the heterogeneity of IEC population, it will be essential to interrogate in detail that whether and how Treg cells regulate different enterocyte subsets for mucosal neuroendocrinal responses beyond intestinal barrier function. The understanding of the cellular and molecular mechanisms responsible for reciprocal regulation between Treg cells and IECs could provide new insights into how Treg cells control tissue homeostasis on different barrier surfaces for development of therapeutic interventions.</p>
</sec>
<sec id="s8" sec-type="author-contributions">
<title>Author Contributions</title>
<p>CW and ZJ wrote the manuscript. All authors contributed to the article and approved the submitted version.</p>
</sec>
<sec id="s9" sec-type="funding-information">
<title>Funding</title>
<p>This work was supported by the Intramural Research Program of the NCI, NIH, United States.</p>
</sec>
<sec id="s10" sec-type="COI-statement">
<title>Conflict of Interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s11" sec-type="disclaimer">
<title>Publisher&#x2019;s Note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
</body>
<back>
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