Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Jose M Gonzalez-Granado
 -- 3085 2023-02-08 12:30:08 |
2 format correct
Catherine Yang
 Meta information modification 3085 2023-02-09 02:20:32 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Gomez-Bris, R.;  Saez, A.;  Herrero-Fernandez, B.;  Rius, C.;  Sanchez-Martinez, H.;  Gonzalez-Granado, J.M. CD4 T-Cell in Inflammatory Bowel Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/40980 (accessed on 16 November 2024).
Gomez-Bris R,  Saez A,  Herrero-Fernandez B,  Rius C,  Sanchez-Martinez H,  Gonzalez-Granado JM. CD4 T-Cell in Inflammatory Bowel Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/40980. Accessed November 16, 2024.
Gomez-Bris, Raquel, Angela Saez, Beatriz Herrero-Fernandez, Cristina Rius, Hector Sanchez-Martinez, Jose M. Gonzalez-Granado. "CD4 T-Cell in Inflammatory Bowel Disease" Encyclopedia, https://encyclopedia.pub/entry/40980 (accessed November 16, 2024).
Gomez-Bris, R.,  Saez, A.,  Herrero-Fernandez, B.,  Rius, C.,  Sanchez-Martinez, H., & Gonzalez-Granado, J.M. (2023, February 08). CD4 T-Cell in Inflammatory Bowel Disease. In Encyclopedia. https://encyclopedia.pub/entry/40980
Gomez-Bris, Raquel, et al. "CD4 T-Cell in Inflammatory Bowel Disease." Encyclopedia. Web. 08 February, 2023.
CD4 T-Cell in Inflammatory Bowel Disease
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms24032696

Inflammatory bowel disease (IBD) is an umbrella term for the chronic immune-mediated idiopathic inflammation of the gastrointestinal tract, manifesting as Crohn’s disease (CD) or ulcerative colitis (UC). IBD is characterized by exacerbated innate and adaptive immunity in the gut in association with microbiota dysbiosis and the disruption of the intestinal barrier, resulting in increased bacterial exposure. In response to signals from microorganisms and damaged tissue, innate immune cells produce inflammatory cytokines and factors that stimulate T and B cells of the adaptive immune system, and a prominent characteristic of IBD patients is the accumulation of inflammatory T-cells and their proinflammatory-associated cytokines in intestinal tissue. Upon antigen recognition and activation, CD4 T-cells differentiate towards a range of distinct phenotypes: T helper(h)1, Th2, Th9, Th17, Th22, T follicular helper (Tfh), and several types of T-regulatory cells (Treg). T-cells are generated according to and adapt to microenvironmental conditions and participate in a complex network of interactions among other immune cells that modulate the further progression of IBD. 

inflammatory bowel disease Th1 Th2 Th17 Th19 Th22 regulatory T-cell Treg

1. T-Cells in IBD

Under steady state conditions, the gut contains scattered interepithelial lymphocytes and innate lymphocytes in the epithelial layer of the intestinal mucosa, with very few CD4 T-cells [1]. In contrast, IBD is associated with an abundance of CD4 T-cells in the epithelial layer of the inflamed intestinal mucosa [2] or with normal numbers of lamina propria and epithelial CD4 T-cells [3][4] but showing increased activation [5][6][7] and phenotypic alterations [8].
T-cells release interleukin (IL)-2, which signals in an autocrine manner via the IL-2 receptor, whose α chain, called CD25, is expressed on T-cells upon antigen recognition and activation. IBD is characterized by elevated numbers of hiCD25+ cells, specifically affecting T-cells in CD and macrophages in UC [9]. Some intestinal CD4 T-cells from CD patients, but not UC patients, also express high levels of the activating natural killer group 2D receptor (NKG2D) [10], whose stimulation in combination with that of the TCR promotes the cytotoxic capacity of CD4 T-cells, plus the release of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-17A [10][11].
CD has usually been considered a type 1-driven disease, with the exacerbated production and activation of Th1 and Th17 cells and an elevated presence of their major cytokines IL-12, IL-23, IFN-γ, and IL-17. In contrast, UC has been designated as type 2-driven inflammation, linked to an elevated participation of Th2 and Th9 cells and their principal cytokines IL-13, IL-5, and IL-9 [12][13].

2. T Helper 1 (Th1) Cells

Th1 cells facilitate the eradication of intracellular pathogens, including parasites, protozoa, viruses, and intracellular bacteria, and intervene in cell-mediated immunity and delayed-type hypersensitivity reactions [14]. Th1 cells release IFN-γ and TNF-α, which stimulate innate immune cells, such as neutrophils and macrophages, and non-immune cells, such as epithelial cells and fibroblasts [15][16]. Th1 cells also release IFN-γ and IL-2 to recruit CD8 effector cytotoxic T-cells (CD8 CTL) [17].
Upon antigen recognition and the activation of a naïve CD4 T-cell, Th1 differentiation is mediated by the binding of IL-12 produced by the cognate APC. IL-12 induces T-cell expression of the master Th1 transcription factor T-box-containing protein (T-bet), encoded by the gene TBX21, and the cytokine IFN-γ, in both cases through a process dependent on STAT4 signaling stimulation [15][16][18]. T-bet increases the expression of IL-12 receptor subunit β2 (IL-12Rβ2), allowing synergistic IL-12 and STAT4 signaling to further increase IFN-γ generation [19][20][21].
In intestinal homeostasis, Th1 cells can prevent pathogen invasion and pathogen-derived antigens from mediating intestinal inflammation. Beside their direct antibacterial action, Th1 cells also ameliorate intestinal inflammation by secreting IL-2 and IL-10 to promote Treg stimulation. Moreover, Th1 cells can facilitate intestinal stem cell (ISC) proliferation and intraepithelial cell self-restoration by releasing low concentrations of TNF-α. Th1 cells thus constitute an immune barrier indispensable for intestinal homeostasis [22].
A pathogenic role for Th1 cells has been described in the course of IBD (Figure 1). An excessive Th1 response has been observed in the inflamed mucosa and serum of IBD patients [23]. Classically, an exacerbated Th1 response has been linked to CD, whereas UC has been considered a Th2 cell-driven disease [24]. However, both UC and CD feature activated effector Th1 cells, suggesting that Th1 cells are implicated in the origin and development of mucosal inflammation in IBD [25].
Figure 1. T-cell subsets and functions in the intestinal mucosa in inflammatory bowel disease. The development of IBD is induced by multiple phenomena occurring in the gastrointestinal tract: microbial dysbiosis, disruption of the mucus layer, dysregulation of epithelial tight junctions, defects in the number and function of Paneth cells, and increased intestinal permeability. These events massively increase bacterial exposure. In this context, antigen-bearing DCs capture antigens and migrate to secondary lymphoid organs, where they present antigens to naive T-cells. Once activated, CD4 T-cells undergo proliferation and differentiation into different effector T-cell subsets (Th1, Th9, Th17, and Th2 cells). Differentiated Th cells migrate back to the gut, where they carry out inflammatory functions, such as production of IFN-γ in the case of Th1 cells or IL-17A (which plays an important role in recruiting neutrophils to sites of active inflammation) and IL-21 (which induces MMP production by stromal cells) in the case of Th17 cells. Cytokines released by Th1 cells favor activation of macrophages, which release TNF-α and trigger epithelial-cell apoptosis. Th9 cells produce IL-9, which can act as a proinflammatory cytokine, activating Th17 cells. The presence of IL-9 is associated with alterations in the expression of tight junctions, and intestinal overproduction of IL-9 is likely to impair epithelial-barrier integrity and compromise tolerance to commensal bacteria, eventually progressing to inflammation. IL-33 is upregulated in UC patients and drives a Th2-like cytokine response. Elevated IL-33 production Th2 cells have also been reported in UC patients. Proinflammatory signals in IBD are counterbalanced by IL-10 produced by Tregs. IL-22 released by Th22 cells maintains intestinal epithelial barrier function. In inflamed intestinal tissue, CD4 T-cells are a major source of IL-22BP, which blocks IL-22 signaling.

3. T Helper 2 (Th2) Cells

Th2 cells participate in the elimination of extracellular microbes and intestinal helminths and support IgE-mediated B-cell responses by secreting IL-4, IL-5, IL-13, and IL-10 [26]. Th2 polarization is mediated by IL-4-ligation–dependent STAT6 signaling and the production of the Th2 master transcription factor GATA binding protein 3 (GATA-3) [27][28]. In addition to IL-4, Th2 cells produce the cytokines IL-5, IL-13, IL-21, and IL-25. Th2 cytokines prevent Th1 differentiation and promote the activation of macrophages [14][15]. Impaired Th2 responses are linked to allergies and asthma [29][30][31][32][33][34].
Oxazolone-induced colitis in mice involves a Th2 response featuring IL-5 and IL-4 production [35]. Another important Th2 cytokine is IL-33, which is elevated in UC patients and in mouse models of colitis induced with trinitrobenzenesulfonic acid (TNBS) or DSS. Moreover, IL-33 and the IL-33 receptor ST2 (suppression of tumorigenicity 2) are associated with IBD risk loci [13][36][37][38][39][40][41][42][43]. A lack of ST2 in mice diminishes colitis, whereas the administration of exogenous IL-33 aggravates the condition. These effects are associated with increased amounts of the Th2 cytokines IL-4, IL-5, and IL-13; major reductions in IL-17 and IFN- γ; damage to the epithelial barrier; and delayed wound recovery in the damaged colonic epithelium [13][36][37][38][41][42][43]. In contrast, IL-33 protects against intestinal inflammation by promoting the differentiation of forkhead box P3 (Foxp3)+ Tregs and innate lymphoid cells (ILCs) and by inducing the expression of amphiregulin [44][45].

4. T Helper 9 (Th9) Cells

Th9 cells, like Th2 cells, intervene in the response to intestinal helminths [46] and have been linked to allergy and autoimmunity [47]. The differentiation of Th9 cells is induced by the concurrent action of IL-4 and transforming growth factor-beta (TGF-β). IL-4 binding to the IL-4 receptor triggers GATA3 transcription and the phosphorylation and dimerization of STAT6, promoting Th2 differentiation, whereas TGF-β activates FOXP3, inducing Treg differentiation [48][49]. In combination, IL-4 and TGF-β induce the production of IL-9 and the polarization of CD4 T-cells towards the Th9 phenotype [50][51][52]. Th9 differentiation depends on multiple transcription factors, including PU.1 and IRF4 [53][54]. Th9 differentiation can also be induced by other molecular combinations [55], such as IL-4 plus IL-1β [56]. Th9 cells are the main source of IL9, but also release IL-10 [51][57]. IL-9 can act as a proinflammatory cytokine, activating Th17 cells [58], and shares the same γ-chain receptor as IL-4, IL-2, and IL-15. IL-9 binding to its receptor activates janus kinase (JAK)1 and JAK3, which form dimers with STAT3, STAT5, or STAT1 [59][60][61].
The contribution of Th9 cells and their role in gut immunity have been demonstrated in several studies. Altered tissue integrity and continuous inflammation during flare-up episodes in UC are associated with IL-9 release by Th9 cells in the colon [62][63]. The presence of Th9-derived IL-9 is associated with alterations in the expression of tight junctions [64].

5. T Helper 17 (Th17) Cells

Th17 cells protect the host from bacterial and fungal infections on mucosal surfaces but are also implicated in inflammatory and autoimmune diseases [65]. Th17 cells have thus been identified as pathogenic cells in relation to tissue inflammation and autoimmune disease [66][67][68]. However, it is becoming clear that Th17 cells also have a non-pathogenic phenotype with immune-modulatory functions [22][69][70][71][72].
Pathogenic and non-pathogenic Th17 cells can be polarized in vitro [73]. A combination of IL-6, IL-23, and IL-1β promotes pathogenic Th17 differentiation [74][75], whereas TGF-β1, in addition to IL-6, favors non-pathogenic Th17 cells [69][76][77][78]. IL-23 appears not to promote Th17  differentiation directly since naïve T-cells do not express the IL-23 receptor (IL-23R) in vitro, thus suggesting that IL-23 stabilizes the Th17 phenotype and promotes Th17 cell survival [75].
Pathogenic and non-pathogenic Th17 cells both express the transcription factor retinoic acid receptor-related orphan nuclear receptor gamma (RORγt) [79] in a STAT3-dependent manner [80] and produce IL-17 [22]; however, they have distinct genetic signatures, one contributing to immune injury and the other to immune homeostasis [73][81]. Pathogenic Th17 cells are characterized by the production of pro-inflammatory molecules, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-23R, and by a low expression of immune-regulatory molecules, such as IL-10 and CD5 molecule like (CD5L). In contrast, non-pathogenic Th17 cells produce low amounts of GM-CSF and IL-23R and high amounts of IL-10 and CD5L, facilitating tissue homeostasis [69][70][75][82][83].
Th17 cells are more numerous in the peripheral blood of IBD patients, and several major Th17 cytokines, such as IL-17, IL-21, and IL-23, are abundant in the inflamed mucosa of these patients [84].
IL-17 also modulates anti-microbial peptide release, potentially modulating microbial populations within the gut in IBD [85]. IL-17, in concert with fibroblast growth factor 2, also controls both epithelial barrier maintenance and bacterial homeostasis in the intestine [86]. Together, these data indicate a proinflammatory effect of Th17 in concert with a role in maintaining a healthy epithelial barrier and an optimal bacterial balance.
IL-23 promotes the expansion of pathogenic Th17 cells by maintaining Th17 signature genes, upregulating effector genes, such as IL17A, IL17F, or IL22, or repressing suppressive factors. Moreover, IL17 and IL23 signaling promote pro-inflammatory molecules such as TNF, IFNγ, IL22, lymphotoxin, and IL1β [87]. Several mouse models of colitis have shown an augmented production of IL23 [88][89][90][91]. In patients, treatment with selective IL23 inhibitors promotes better response rates in the cohort of CD patients that failed prior anti-TNF therapy (reviewed in [87]), and IL23 targeting in UC patient, is safe and effective and promote and sustain clinical remission, low inflammation, mucosal healing, and an improved quality of life (reviewed in [92]). These experiments indicate the importance of the IL23/IL17 axis in mucosal inflammation.

6. T Helper 22 (Th22) Cells

Th22 cells protect against tissue damage and bacterial infection by producing the IL-10 family member IL-22 [93][94][95]. Th22 cells also produce IL-13, fibroblast growth factor, chemokines, and TNFα. IL-22 is also secreted by Th1 and Th17 cells, but Th22 cells are able to secrete IL-22 without producing IFN-γ or IL-17 [14][96]. IL-22 is also secreted by NKs, γδT cells, ILC3s, and some nonlymphoid cells [97]. Th22 cells express the chemokine receptors CCR10, CCR6, and CCR4, and their differentiation is promoted by the activation of STAT3 and the aryl hydrocarbon receptor (AHR) by IL-6, TNF-α, and IL-1β and is diminished by TGF-β [98][99].
IL-22 enhances innate immunity by modulating cell differentiation, chemokine secretion, and antimicrobial peptide (AMP) secretion [100][101][102]. In the intestinal epithelium, IL-22 promotes the secretion of AMPs, such as β defensins and lipocalin 2 and the mucin proteins MUC1 and MUC3 [103]. IL-22 can also promote the secretion by human colonic myofibroblasts of the anti-inflammatory factor IL-11 and inflammatory molecules, such as IL-6 and CXCL chemokines [104].
In healthy individuals, IL-22 is released mainly in the gastrointestinal tract, where it favors mucosal recovery [105][106]. This beneficial effect is mediated by the binding of IL-22 to the receptor IL-22R, whose expression is mostly limited to epithelial cells [105].
IL-22 maintains intestinal epithelial barrier function by promoting the release of antimicrobial peptides [93] and mucins [106], as well as by facilitating intestinal epithelial cell survival and proliferation [105]. IL-22 can increase the production of anti-inflammatory factors, such as IL-11, that also protect epithelial barrier function [107].
However, elevated levels of IL-22 can be detrimental [97], enhancing the production of inflammatory mediators, such as IL-6 and CXCL chemokines by human colonic myofibroblasts [108]. IL-22 modulates neutrophil recruitment to the colon by controlling the expression of neutrophil-active CXC-family chemokines in ulcerative colitis; by this mechanism, the augmented expression of IL-22 is associated with treatment resistance to an anti-IL-12/23 p40 subunit monoclonal antibody [109].
IL-22 is secreted at low levels, and is mostly maintained in a biologically inactive state through the action of IL-22 binding protein (IL-22BP, also known as IL-22RA2), produced by intestinal DCs and macrophages in the gut lamina propria and secondary lymphoid structures [110][111][112][113][114]. In inflamed intestinal tissue, the main producers of IL-22BP are CD4 T-cells [108][111]. IL-22BP is a soluble receptor homolog that attaches to IL-22 with greater affinity than IL-22R, preventing IL-22 from binding to its receptor and thereby blocking IL-22 signaling [115][116]. Elevated levels of IL-22 and IL-22BP mRNA and protein have been detected in inflamed tissue from CD and UC patients [111][117][118]. Consistent with these findings, the IL-22-associated protection against DSS-induced colitis is increased in IL-22BP deficient rats [119], and IL-22BP aggravates T-cell-mediated colitis in mice [111]. IL-22BP expression is reduced in infectious colitis but not in inflamed tissues in IBD, indicating potential pathophysiological significance for IL-22BP-dependent alterations in IL-22 bioactivity [111][119].These responses may vary between patients and differ according to the extent of histological damage. For example, CD patients with granuloma are reported to have increased frequencies of IL-22+ and IL-22+ IFN-γ+ cells in colonic tissue [120].

7. Regulatory T-Cells (Treg)

Treg cells suppress immune responses and maintain peripheral tolerance and immune homeostasis [121]. Tregs are divided into thymic-derived Tregs, also called natural Treg cells (nTregs) [122], and post-thymic maturation peripheral Tregs (pTregs) [123][124][125][126][127]. Tregs induced in vitro by the addition of TGF-β and IL-2 to naïve CD4 T-cells are called inducible Tregs (iTregs) [127][128].
Tregs are characterized by the secretion of the inhibitory cytokines IL-10, IL-35, and TGF-β, and the expression of the transcription factor Foxp3, which mediates Treg development, lineage commitment, and regulatory functions [15]. Another marker of nTregs and pTregs is the IL-2 receptor α chain CD25 [15].
nTregs are positively selected in the thymus by the intermediate affinity of the TCR for self-peptides/MHC [122], whereas T-cells with a high-affinity TCR antigen are eliminated and those with low-affinity differentiate into naïve T-cells [129]. In humans, nTreg development seems to also depend on IL-2 and/or IL-15 [130][131][132].
In the thymus, a restricted number of autoreactive CD4 T-cells differentiate into nTregs, in a process called agonist selection that guarantees central tolerance to self-antigens, thus avoiding autoimmunity [126][133][134]. nTregs are already in an antigen-primed or antigen-activated state in the thymus [128].
pTregs differentiate from conventional CD4 T-cells in the periphery under tolerogenic conditions in secondary lymphoid tissues, in particular intestinal draining lymph nodes, upon the recognition of an antigen presented by an APC [135][136][137]. pTreg differentiation requires the sustained expression of FOXP3 and is dependent on high levels of TGF-β, an absence of proinflammatory cytokines [14], and the activation of naïve CD4 T-cells upon recognition of mainly exogenous antigens [138][139][140]. pTreg differentiation is also facilitated by vitamin-A derived retinoic acid [141][142][143].
pTregs are classified as central, effector, and tissue-resident pTregs [144]. Central pTregs are considered naïve and in mice are characterized by the expression of the markers CD62Lhigh CCR7+ or CD45RAhigh CD25low. Central pTregs are the main Treg type in the circulation and in secondary lymphoid organs. The marker profile of effector Tregs, also called effector memory or activated Tregs, is CD62Llow, CCR7low, CD44hi killer cell lectin like receptor G1 (KLRG1)+, CD103+, or CD25RAlow CD25hi. Effector memory pTregs are less frequent than central pTregs and are similar to conventional activated CD4 T-cells that have had recent contact with an antigen. Tissue-resident pTregs found In non-lymphoid tissues, such as the colon, and under steady state conditions account for most pTregs in the intestine [144].
Tregs are activated at much lower antigen/MHC concentrations than naïve T-cells, ensuring Treg-dependent self-tolerance [145]. Tregs are a frequent immune cell population in the intestine, where they limit inflammatory CD4 T-cells [146][147] and maintain immune homeostasis through several mechanisms [148]. FoxP3+ Tregs, especially effector Tregs, are constantly proliferating under steady state conditions, likely as a consequence of identifying self-antigens and antigens derived from commensal microbes [149][150].
The suppressor activity of Tregs is mostly mediated by cell-contact–dependent and humoral-factor–mediated mechanisms. These mechanisms include IL-2 scavenging; the secretion of regulatory cytokines, such as IL-10, [151], IL-35 [152], and TGF-β [153][154]; the surface expression of inhibitory molecules, such as CTLA-4 (cytotoxic lymphocyte antigen 4) and PD-1 (programmed cell death 1), TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains), CD39, and CD73 [155][156]; cytolysis; and metabolic control [128]. Tregs also promote tissue through the release of growth factor amphiregulin [157].
In the intestine, Tregs can acquire several phenotypes expressing varying levels of GATA3, Helios, and RORγt. GATA3+Helios+ Tregs seem to have a thymic origin and react to the alarmin IL-33 produced in response to tissue damage, reducing tissue injury in colitis [158]. RORγt+Helios− Tregs, produced in response to intestinal microbiota, are considered pTregs and play a protective role in severe gut inflammation [159][160]. RORγt−Helios− Tregs are more abundant in the small intestine and participate in the amelioration of allergic responses to food antigens [161]. These observations indicate that Tregs are highly versatile cells that adapt to their environment in order to better contribute to tissue homeostasis. There is some interest in developing therapies to boost Treg cell number and function and thereby reduce intestinal inflammation in IBD [144][162][163].
Other CD4 T-cell subsets include Foxp3- type 1 regulatory T (Tr1) cells, which secrete the suppressive cytokines IL-10 and TGF β [19][164], and Tfh cells, which are a specialized CD4 T-cell subset involved in the induction and differentiation of B cells into plasma cells and memory cells [165][166][167], cell subsets whose role in IBD has recently been reviewed [19][144][168][169].

References

  1. Allaire, J.M.; Crowley, S.M.; Law, H.T.; Chang, S.Y.; Ko, H.J.; Vallance, B.A. The Intestinal Epithelium: Central Coordinator of Mucosal Immunity. Trends Immunol. 2018, 39, 677–696.
  2. Basso, L.; Boue, J.; Auge, C.; Deraison, C.; Blanpied, C.; Cenac, N.; Lluel, P.; Vergnolle, N.; Dietrich, G. Mobilization of CD4+ T lymphocytes in inflamed mucosa reduces pain in colitis mice: Toward a vaccinal strategy to alleviate inflammatory visceral pain. Pain 2018, 159, 331–341.
  3. Hirata, I.; Berrebi, G.; Austin, L.L.; Keren, D.F.; Dobbins, W.O., 3rd. Immunohistological characterization of intraepithelial and lamina propria lymphocytes in control ileum and colon and in inflammatory bowel disease. Dig. Dis. Sci. 1986, 31, 593–603.
  4. Selby, W.S.; Janossy, G.; Bofill, M.; Jewell, D.P. Intestinal lymphocyte subpopulations in inflammatory bowel disease: An analysis by immunohistological and cell isolation techniques. Gut 1984, 25, 32–40.
  5. Schreiber, S.; MacDermott, R.P.; Raedler, A.; Pinnau, R.; Bertovich, M.J.; Nash, G.S. Increased activation of isolated intestinal lamina propria mononuclear cells in inflammatory bowel disease. Gastroenterology 1991, 101, 1020–1030.
  6. Rabe, H.; Malmquist, M.; Barkman, C.; Ostman, S.; Gjertsson, I.; Saalman, R.; Wold, A.E. Distinct patterns of naive, activated and memory T and B cells in blood of patients with ulcerative colitis or Crohn’s disease. Clin. Exp. Immunol. 2019, 197, 111–129.
  7. Muller, S.; Lory, J.; Corazza, N.; Griffiths, G.M.; Z’Graggen, K.; Mazzucchelli, L.; Kappeler, A.; Mueller, C. Activated CD4+ and CD8+ cytotoxic cells are present in increased numbers in the intestinal mucosa from patients with active inflammatory bowel disease. Am. J. Pathol. 1998, 152, 261–268.
  8. Corridoni, D.; Antanaviciute, A.; Gupta, T.; Fawkner-Corbett, D.; Aulicino, A.; Jagielowicz, M.; Parikh, K.; Repapi, E.; Taylor, S.; Ishikawa, D.; et al. Single-cell atlas of colonic CD8(+) T cells in ulcerative colitis. Nat. Med. 2020, 26, 1480–1490.
  9. Page, M.J.; Poritz, L.S.; Tilberg, A.F.; Zhang, W.J.; Chorney, M.J.; Koltun, W.A. Cd1d-restricted cellular lysis by peripheral blood lymphocytes: Relevance to the inflammatory bowel diseases. J. Surg. Res. 2000, 92, 214–221.
  10. Allez, M.; Tieng, V.; Nakazawa, A.; Treton, X.; Pacault, V.; Dulphy, N.; Caillat-Zucman, S.; Paul, P.; Gornet, J.M.; Douay, C.; et al. CD4+NKG2D+ T cells in Crohn’s disease mediate inflammatory and cytotoxic responses through MICA interactions. Gastroenterology 2007, 132, 2346–2358.
  11. Pariente, B.; Mocan, I.; Camus, M.; Dutertre, C.A.; Ettersperger, J.; Cattan, P.; Gornet, J.M.; Dulphy, N.; Charron, D.; Lemann, M.; et al. Activation of the receptor NKG2D leads to production of Th17 cytokines in CD4+ T cells of patients with Crohn’s disease. Gastroenterology 2011, 141, 217–226.e2.
  12. de Souza, H.S.; Fiocchi, C. Immunopathogenesis of IBD: Current state of the art. Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 13–27.
  13. Mahapatro, M.; Erkert, L.; Becker, C. Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut. Cells 2021, 10, 111.
  14. Raphael, I.; Nalawade, S.; Eagar, T.N.; Forsthuber, T.G. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 2015, 74, 5–17.
  15. Caza, T.; Landas, S. Functional and Phenotypic Plasticity of CD4(+) T Cell Subsets. Biomed. Res. Int. 2015, 2015, 521957.
  16. Lazarevic, V.; Glimcher, L.H.; Lord, G.M. T-bet: A bridge between innate and adaptive immunity. Nat. Rev. Immunol. 2013, 13, 777–789.
  17. Wang, P.; Zhang, Q.; Tan, L.; Xu, Y.; Xie, X.; Zhao, Y. The Regulatory Effects of mTOR Complexes in the Differentiation and Function of CD4(+) T Cell Subsets. J. Immunol. Res. 2020, 2020, 3406032.
  18. Baumann, C.; Bonilla, W.V.; Frohlich, A.; Helmstetter, C.; Peine, M.; Hegazy, A.N.; Pinschewer, D.D.; Lohning, M. T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses. Proc. Natl. Acad. Sci. USA 2015, 112, 4056–4061.
  19. Tindemans, I.; Joosse, M.E.; Samsom, J.N. Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD. Cells 2020, 9, 110.
  20. Szabo, S.J.; Kim, S.T.; Costa, G.L.; Zhang, X.; Fathman, C.G.; Glimcher, L.H. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000, 100, 655–669.
  21. Yang, R.; Mele, F.; Worley, L.; Langlais, D.; Rosain, J.; Benhsaien, I.; Elarabi, H.; Croft, C.A.; Doisne, J.M.; Zhang, P.; et al. Human T-bet Governs Innate and Innate-like Adaptive IFN-gamma Immunity against Mycobacteria. Cell 2020, 183, 1826–1847.e31.
  22. Wu, X.; Tian, J.; Wang, S. Insight Into Non-Pathogenic Th17 Cells in Autoimmune Diseases. Front. Immunol. 2018, 9, 1112.
  23. Leppkes, M.; Neurath, M.F. Cytokines in inflammatory bowel diseases—Update 2020. Pharmacol. Res. 2020, 158, 104835.
  24. Li, J.; Ueno, A.; Fort Gasia, M.; Luider, J.; Wang, T.; Hirota, C.; Jijon, H.B.; Deane, M.; Tom, M.; Chan, R.; et al. Profiles of Lamina Propria T Helper Cell Subsets Discriminate Between Ulcerative Colitis and Crohn’s Disease. Inflamm. Bowel Dis. 2016, 22, 1779–1792.
  25. Ma, C.; Wu, W.; Lin, R.; Ge, Y.; Zhang, C.; Sun, S.; Cong, Y.; Li, X.; Liu, Z. Critical Role of CD6highCD4+ T Cells in Driving Th1/Th17 Cell Immune Responses and Mucosal Inflammation in IBD. J. Crohns Colitis 2019, 13, 510–524.
  26. Zeng, W.P. ‘All things considered’: Transcriptional regulation of T helper type 2 cell differentiation from precursor to effector activation. Immunology 2013, 140, 31–38.
  27. Zheng, W.; Flavell, R.A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 1997, 89, 587–596.
  28. Zhang, D.H.; Cohn, L.; Ray, P.; Bottomly, K.; Ray, A. Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J. Biol. Chem. 1997, 272, 21597–21603.
  29. Bryant, N.; Muehling, L.M. T-cell responses in asthma exacerbations. Ann. Allergy Asthma Immunol. 2022, 129, 709–718.
  30. Shankar, A.; McAlees, J.W.; Lewkowich, I.P. Modulation of IL-4/IL-13 cytokine signaling in the context of allergic disease. J. Allergy Clin. Immunol. 2022, 150, 266–276.
  31. Luo, W.; Hu, J.; Xu, W.; Dong, J. Distinct spatial and temporal roles for Th1, Th2, and Th17 cells in asthma. Front. Immunol. 2022, 13, 974066.
  32. Habib, N.; Pasha, M.A.; Tang, D.D. Current Understanding of Asthma Pathogenesis and Biomarkers. Cells 2022, 11, 2764.
  33. Salvati, L.; Liotta, F.; Annunziato, F.; Cosmi, L. Therapeutical Targets in Allergic Inflammation. Biomedicines 2022, 10, 2874.
  34. Durham, S.R.; Shamji, M.H. Allergen immunotherapy: Past, present and future. Nat. Rev. Immunol. 2022, 1–12.
  35. Boirivant, M.; Fuss, I.J.; Chu, A.; Strober, W. Oxazolone colitis: A murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J. Exp. Med. 1998, 188, 1929–1939.
  36. Pushparaj, P.N.; Li, D.; Komai-Koma, M.; Guabiraba, R.; Alexander, J.; McSharry, C.; Xu, D. Interleukin-33 exacerbates acute colitis via interleukin-4 in mice. Immunology 2013, 140, 70–77.
  37. Sedhom, M.A.K.; Pichery, M.; Murdoch, J.R.; Foligné, B.; Ortega, N.; Normand, S.; Mertz, K.; Sanmugalingam, D.; Brault, L.; Grandjean, T.; et al. Neutralisation of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice. Gut 2013, 62, 1714–1723.
  38. Guan, Q.; Zhang, J. Recent Advances: The Imbalance of Cytokines in the Pathogenesis of Inflammatory Bowel Disease. Mediat. Inflamm. 2017, 2017, 4810258.
  39. Pastorelli, L.; De Salvo, C.; Vecchi, M.; Pizarro, T.T. The role of IL-33 in gut mucosal inflammation. Mediat. Inflamm. 2013, 2013, 608187.
  40. Latiano, A.; Palmieri, O.; Pastorelli, L.; Vecchi, M.; Pizarro, T.T.; Bossa, F.; Merla, G.; Augello, B.; Latiano, T.; Corritore, G.; et al. Associations between genetic polymorphisms in IL-33, IL1R1 and risk for inflammatory bowel disease. PLoS ONE 2013, 8, e62144.
  41. Zhu, J.; Wang, Y.; Yang, F.; Sang, L.; Zhai, J.; Li, S.; Li, Y.; Wang, D.; Lu, C.; Sun, X. IL-33 alleviates DSS-induced chronic colitis in C57BL/6 mice colon lamina propria by suppressing Th17 cell response as well as Th1 cell response. Int. Immunopharmacol. 2015, 29, 846–853.
  42. Zhu, J.; Xu, Y.; Zhu, C.; Zhao, J.; Meng, X.; Chen, S.; Wang, T.; Li, X.; Zhang, L.; Lu, C.; et al. IL-33 induces both regulatory B cells and regulatory T cells in dextran sulfate sodium-induced colitis. Int. Immunopharmacol. 2017, 46, 38–47.
  43. Zhu, J.; Yang, F.; Sang, L.; Zhai, J.; Zhang, X.; Yue, D.; Li, S.; Li, Y.; Lu, C.; Sun, X. IL-33 Aggravates DSS-Induced Acute Colitis in Mouse Colon Lamina Propria by Enhancing Th2 Cell Responses. Mediat. Inflamm. 2015, 2015, 913041.
  44. Monticelli, L.A.; Osborne, L.C.; Noti, M.; Tran, S.V.; Zaiss, D.M.; Artis, D. IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions. Proc. Natl. Acad. Sci. USA 2015, 112, 10762–10767.
  45. Duan, L.; Chen, J.; Zhang, H.; Yang, H.; Zhu, P.; Xiong, A.; Xia, Q.; Zheng, F.; Tan, Z.; Gong, F.; et al. Interleukin-33 ameliorates experimental colitis through promoting Th2/Foxp3(+) regulatory T-cell responses in mice. Mol. Med. 2012, 18, 753–761.
  46. Schmitt, E.; Bopp, T. Discovery and initial characterization of Th9 cells: The early years. Semin. Immunopathol. 2017, 39, 5–10.
  47. Neurath, M.F.; Finotto, S. IL-9 signaling as key driver of chronic inflammation in mucosal immunity. Cytokine Growth Factor Rev. 2016, 29, 93–99.
  48. Kaplan, M.H.; Schindler, U.; Smiley, S.T.; Grusby, M.J. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 1996, 4, 313–319.
  49. Lu, L.; Ma, J.; Wang, X.; Wang, J.; Zhang, F.; Yu, J.; He, G.; Xu, B.; Brand, D.D.; Horwitz, D.A.; et al. Synergistic effect of TGF-beta superfamily members on the induction of Foxp3+ Treg. Eur. J. Immunol. 2010, 40, 142–152.
  50. Veldhoen, M.; Uyttenhove, C.; van Snick, J.; Helmby, H.; Westendorf, A.; Buer, J.; Martin, B.; Wilhelm, C.; Stockinger, B. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 2008, 9, 1341–1346.
  51. Dardalhon, V.; Awasthi, A.; Kwon, H.; Galileos, G.; Gao, W.; Sobel, R.A.; Mitsdoerffer, M.; Strom, T.B.; Elyaman, W.; Ho, I.C.; et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(−) effector T cells. Nat. Immunol. 2008, 9, 1347–1355.
  52. Cosmi, L.; Maggi, L.; Santarlasci, V.; Liotta, F.; Annunziato, F. T helper cells plasticity in inflammation. Cytom. Part A J. Int. Soc. Anal. Cytol. 2014, 85, 36–42.
  53. Staudt, V.; Bothur, E.; Klein, M.; Lingnau, K.; Reuter, S.; Grebe, N.; Gerlitzki, B.; Hoffmann, M.; Ulges, A.; Taube, C.; et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 2010, 33, 192–202.
  54. Chang, H.C.; Sehra, S.; Goswami, R.; Yao, W.; Yu, Q.; Stritesky, G.L.; Jabeen, R.; McKinley, C.; Ahyi, A.N.; Han, L.; et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat. Immunol. 2010, 11, 527–534.
  55. Shohan, M.; Elahi, S.; Shirzad, H.; Rafieian-Kopaei, M.; Bagheri, N.; Soltani, E. Th9 Cells: Probable players in ulcerative colitis pathogenesis. Int. Rev. Immunol. 2018, 37, 192–205.
  56. Xue, G.; Jin, G.; Fang, J.; Lu, Y. IL-4 together with IL-1beta induces antitumor Th9 cell differentiation in the absence of TGF-beta signaling. Nat. Commun. 2019, 10, 1376.
  57. Wilhelm, C.; Turner, J.E.; Van Snick, J.; Stockinger, B. The many lives of IL-9: A question of survival? Nat. Immunol. 2012, 13, 637–641.
  58. Schmitt, N.; Ueno, H. Regulation of human helper T cell subset differentiation by cytokines. Curr. Opin. Immunol. 2015, 34, 130–136.
  59. Bauer, J.H.; Liu, K.D.; You, Y.; Lai, S.Y.; Goldsmith, M.A. Heteromerization of the gammac chain with the interleukin-9 receptor alpha subunit leads to STAT activation and prevention of apoptosis. J. Biol. Chem. 1998, 273, 9255–9260.
  60. Demoulin, J.B.; Uyttenhove, C.; Van Roost, E.; DeLestre, B.; Donckers, D.; Van Snick, J.; Renauld, J.C. A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9. Mol. Cell. Biol. 1996, 16, 4710–4716.
  61. Demoulin, J.B.; Van Roost, E.; Stevens, M.; Groner, B.; Renauld, J.C. Distinct roles for STAT1, STAT3, and STAT5 in differentiation gene induction and apoptosis inhibition by interleukin-9. J. Biol. Chem. 1999, 274, 25855–25861.
  62. Gerlach, K.; Hwang, Y.; Nikolaev, A.; Atreya, R.; Dornhoff, H.; Steiner, S.; Lehr, H.A.; Wirtz, S.; Vieth, M.; Waisman, A.; et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat. Immunol. 2014, 15, 676–686.
  63. Gerlach, K.; McKenzie, A.N.; Neurath, M.F.; Weigmann, B. IL-9 regulates intestinal barrier function in experimental T cell-mediated colitis. Tissue Barriers 2015, 3, e983777.
  64. Turner, J.R. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 2009, 9, 799–809.
  65. Acharya, S.; Timilshina, M.; Jiang, L.; Neupane, S.; Choi, D.Y.; Park, S.W.; Lee, S.Y.; Jeong, B.S.; Kim, J.A.; Nam, T.G.; et al. Amelioration of Experimental autoimmune encephalomyelitis and DSS induced colitis by NTG-A-009 through the inhibition of Th1 and Th17 cells differentiation. Sci. Rep. 2018, 8, 7799.
  66. Korn, T.; Bettelli, E.; Oukka, M.; Kuchroo, V.K. IL-17 and Th17 Cells. Annu. Rev. Immunol. 2009, 27, 485–517.
  67. Dong, C. Diversification of T-helper-cell lineages: Finding the family root of IL-17-producing cells. Nat. Rev. Immunol. 2006, 6, 329–333.
  68. Weaver, C.T.; Harrington, L.E.; Mangan, P.R.; Gavrieli, M.; Murphy, K.M. Th17: An effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006, 24, 677–688.
  69. McGeachy, M.J.; Bak-Jensen, K.S.; Chen, Y.; Tato, C.M.; Blumenschein, W.; McClanahan, T.; Cua, D.J. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat. Immunol. 2007, 8, 1390–1397.
  70. Omenetti, S.; Bussi, C.; Metidji, A.; Iseppon, A.; Lee, S.; Tolaini, M.; Li, Y.; Kelly, G.; Chakravarty, P.; Shoaie, S.; et al. The Intestine Harbors Functionally Distinct Homeostatic Tissue-Resident and Inflammatory Th17 Cells. Immunity 2019, 51, 77–89.e6.
  71. Esplugues, E.; Huber, S.; Gagliani, N.; Hauser, A.E.; Town, T.; Wan, Y.Y.; O’Connor, W., Jr.; Rongvaux, A.; Van Rooijen, N.; Haberman, A.M.; et al. Control of TH17 cells occurs in the small intestine. Nature 2011, 475, 514–518.
  72. Noster, R.; de Koning, H.D.; Maier, E.; Prelog, M.; Lainka, E.; Zielinski, C.E. Dysregulation of proinflammatory versus anti-inflammatory human T(H)17 cell functionalities in the autoinflammatory Schnitzler syndrome. J. Allergy Clin. Immunol. 2016, 138, 1161–1169.e6.
  73. Stockinger, B.; Omenetti, S. The dichotomous nature of T helper 17 cells. Nat. Rev. Immunol. 2017, 17, 535–544.
  74. Ghoreschi, K.; Laurence, A.; Yang, X.P.; Tato, C.M.; McGeachy, M.J.; Konkel, J.E.; Ramos, H.L.; Wei, L.; Davidson, T.S.; Bouladoux, N.; et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 2010, 467, 967–971.
  75. Lee, Y.; Awasthi, A.; Yosef, N.; Quintana, F.J.; Xiao, S.; Peters, A.; Wu, C.; Kleinewietfeld, M.; Kunder, S.; Hafler, D.A.; et al. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 2012, 13, 991–999.
  76. Mangan, P.R.; Harrington, L.E.; O’Quinn, D.B.; Helms, W.S.; Bullard, D.C.; Elson, C.O.; Hatton, R.D.; Wahl, S.M.; Schoeb, T.R.; Weaver, C.T. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006, 441, 231–234.
  77. Bettelli, E.; Carrier, Y.; Gao, W.; Korn, T.; Strom, T.B.; Oukka, M.; Weiner, H.L.; Kuchroo, V.K. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006, 441, 235–238.
  78. 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.
  79. Tesmer, L.A.; Lundy, S.K.; Sarkar, S.; Fox, D.A. Th17 cells in human disease. Immunol. Rev. 2008, 223, 87–113.
  80. Yang, X.O.; Panopoulos, A.D.; Nurieva, R.; Chang, S.H.; Wang, D.; Watowich, S.S.; Dong, C. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 2007, 282, 9358–9363.
  81. Ghoreschi, K.; Laurence, A.; Yang, X.P.; Hirahara, K.; O’Shea, J.J. T helper 17 cell heterogeneity and pathogenicity in autoimmune disease. Trends Immunol. 2011, 32, 395–401.
  82. Wang, C.; Yosef, N.; Gaublomme, J.; Wu, C.; Lee, Y.; Clish, C.B.; Kaminski, J.; Xiao, S.; Meyer Zu Horste, G.; Pawlak, M.; et al. CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity. Cell 2015, 163, 1413–1427.
  83. Gaublomme, J.T.; Yosef, N.; Lee, Y.; Gertner, R.S.; Yang, L.V.; Wu, C.; Pandolfi, P.P.; Mak, T.; Satija, R.; Shalek, A.K.; et al. Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell 2015, 163, 1400–1412.
  84. Raza, A.; Shata, M.T. Letter: Pathogenicity of Th17 cells may differ in ulcerative colitis compared with Crohn’s disease. Aliment. Pharmacol. Ther. 2012, 36, 204.
  85. Maxwell, J.R.; Zhang, Y.; Brown, W.A.; Smith, C.L.; Byrne, F.R.; Fiorino, M.; Stevens, E.; Bigler, J.; Davis, J.A.; Rottman, J.B.; et al. Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation. Immunity 2015, 43, 739–750.
  86. Song, X.; Dai, D.; He, X.; Zhu, S.; Yao, Y.; Gao, H.; Wang, J.; Qu, F.; Qiu, J.; Wang, H.; et al. Growth Factor FGF2 Cooperates with Interleukin-17 to Repair Intestinal Epithelial Damage. Immunity 2015, 43, 488–501.
  87. Schmitt, H.; Neurath, M.F.; Atreya, R. Role of the IL23/IL17 Pathway in Crohn’s Disease. Front. Immunol. 2021, 12, 622934.
  88. Arnold, I.C.; Mathisen, S.; Schulthess, J.; Danne, C.; Hegazy, A.N.; Powrie, F. CD11c(+) monocyte/macrophages promote chronic Helicobacter hepaticus-induced intestinal inflammation through the production of IL-23. Mucosal Immunol. 2016, 9, 352–363.
  89. Becker, C.; Dornhoff, H.; Neufert, C.; Fantini, M.C.; Wirtz, S.; Huebner, S.; Nikolaev, A.; Lehr, H.A.; Murphy, A.J.; Valenzuela, D.M.; et al. Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J. Immunol. 2006, 177, 2760–2764.
  90. Yen, D.; Cheung, J.; Scheerens, H.; Poulet, F.; McClanahan, T.; McKenzie, B.; Kleinschek, M.A.; Owyang, A.; Mattson, J.; Blumenschein, W.; et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Investig. 2006, 116, 1310–1316.
  91. Karaboga, I.; Demirtas, S.; Karaca, T. Investigation of the relationship between the Th17/IL-23 pathway and innate-adaptive immune system in TNBS-induced colitis in rats. Iran. J. Basic Med. Sci. 2017, 20, 870–879.
  92. Noviello, D.; Mager, R.; Roda, G.; Borroni, R.G.; Fiorino, G.; Vetrano, S. The IL23-IL17 Immune Axis in the Treatment of Ulcerative Colitis: Successes, Defeats, and Ongoing Challenges. Front. Immunol. 2021, 12, 611256.
  93. Zheng, Y.; Valdez, P.A.; Danilenko, D.M.; Hu, Y.; Sa, S.M.; Gong, Q.; Abbas, A.R.; Modrusan, Z.; Ghilardi, N.; de Sauvage, F.J.; et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 2008, 14, 282–289.
  94. Pickert, G.; Neufert, C.; Leppkes, M.; Zheng, Y.; Wittkopf, N.; Warntjen, M.; Lehr, H.A.; Hirth, S.; Weigmann, B.; Wirtz, S.; et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 2009, 206, 1465–1472.
  95. Basu, R.; O’Quinn, D.B.; Silberger, D.J.; Schoeb, T.R.; Fouser, L.; Ouyang, W.; Hatton, R.D.; Weaver, C.T. Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 2012, 37, 1061–1075.
  96. Dudakov, J.A.; Mertelsmann, A.M.; O’Connor, M.H.; Jenq, R.R.; Velardi, E.; Young, L.F.; Smith, O.M.; Boyd, R.L.; van den Brink, M.R.M.; Hanash, A.M. Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease. Blood 2017, 130, 933–942.
  97. Shohan, M.; Dehghani, R.; Khodadadi, A.; Dehnavi, S.; Ahmadi, R.; Joudaki, N.; Houshmandfar, S.; Shamshiri, M.; Shojapourian, S.; Bagheri, N. Interleukin-22 and intestinal homeostasis: Protective or destructive? IUBMB Life 2020, 72, 1585–1602.
  98. Plank, M.W.; Kaiko, G.E.; Maltby, S.; Weaver, J.; Tay, H.L.; Shen, W.; Wilson, M.S.; Durum, S.K.; Foster, P.S. Th22 Cells Form a Distinct Th Lineage from Th17 Cells In Vitro with Unique Transcriptional Properties and Tbet-Dependent Th1 Plasticity. J. Immunol. 2017, 198, 2182–2190.
  99. Duhen, T.; Geiger, R.; Jarrossay, D.; Lanzavecchia, A.; Sallusto, F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol. 2009, 10, 857–863.
  100. Li, J.; Chen, S.; Xiao, X.; Zhao, Y.; Ding, W.; Li, X.C. IL-9 and Th9 cells in health and diseases-From tolerance to immunopathology. Cytokine Growth Factor Rev. 2017, 37, 47–55.
  101. Mock, B.A.; Krall, M.; Kozak, C.A.; Nesbitt, M.N.; McBride, O.W.; Renauld, J.C.; Van Snick, J. IL9 maps to mouse chromosome 13 and human chromosome 5. Immunogenetics 1990, 31, 265–270.
  102. Stassen, M.; Schmitt, E.; Bopp, T. From interleukin-9 to T helper 9 cells. Ann. N. Y. Acad. Sci. 2012, 1247, 56–68.
  103. Steenwinckel, V.; Louahed, J.; Orabona, C.; Huaux, F.; Warnier, G.; McKenzie, A.; Lison, D.; Levitt, R.; Renauld, J.C. IL-13 mediates in vivo IL-9 activities on lung epithelial cells but not on hematopoietic cells. J. Immunol. 2007, 178, 3244–3251.
  104. Arshad, T.; Mansur, F.; Palek, R.; Manzoor, S.; Liska, V. A Double Edged Sword Role of Interleukin-22 in Wound Healing and Tissue Regeneration. Front. Immunol. 2020, 11, 2148.
  105. Lindemans, C.A.; Calafiore, M.; Mertelsmann, A.M.; O’Connor, M.H.; Dudakov, J.A.; Jenq, R.R.; Velardi, E.; Young, L.F.; Smith, O.M.; Lawrence, G.; et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 2015, 528, 560–564.
  106. Sugimoto, K.; Ogawa, A.; Mizoguchi, E.; Shimomura, Y.; Andoh, A.; Bhan, A.K.; Blumberg, R.S.; Xavier, R.J.; Mizoguchi, A. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Investig. 2008, 118, 534–544.
  107. Gibson, D.L.; Montero, M.; Ropeleski, M.J.; Bergstrom, K.S.; Ma, C.; Ghosh, S.; Merkens, H.; Huang, J.; Mansson, L.E.; Sham, H.P.; et al. Interleukin-11 reduces TLR4-induced colitis in TLR2-deficient mice and restores intestinal STAT3 signaling. Gastroenterology 2010, 139, 1277–1288.
  108. Andoh, A.; Zhang, Z.; Inatomi, O.; Fujino, S.; Deguchi, Y.; Araki, Y.; Tsujikawa, T.; Kitoh, K.; Kim-Mitsuyama, S.; Takayanagi, A.; et al. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 2005, 129, 969–984.
  109. Pavlidis, P.; Tsakmaki, A.; Pantazi, E.; Li, K.; Cozzetto, D.; Digby-Bell, J.; Yang, F.; Lo, J.W.; Alberts, E.; Sa, A.C.C.; et al. Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy. Nat. Commun. 2022, 13, 5820.
  110. Huber, S.; Gagliani, N.; Zenewicz, L.A.; Huber, F.J.; Bosurgi, L.; Hu, B.; Hedl, M.; Zhang, W.; O’Connor, W., Jr.; Murphy, A.J.; et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 2012, 491, 259–263.
  111. Pelczar, P.; Witkowski, M.; Perez, L.G.; Kempski, J.; Hammel, A.G.; Brockmann, L.; Kleinschmidt, D.; Wende, S.; Haueis, C.; Bedke, T.; et al. A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease. Science 2016, 354, 358–362.
  112. Jinnohara, T.; Kanaya, T.; Hase, K.; Sakakibara, S.; Kato, T.; Tachibana, N.; Sasaki, T.; Hashimoto, Y.; Sato, T.; Watarai, H.; et al. IL-22BP dictates characteristics of Peyer’s patch follicle-associated epithelium for antigen uptake. J. Exp. Med. 2017, 214, 1607–1618.
  113. Martin, J.C.; Beriou, G.; Heslan, M.; Chauvin, C.; Utriainen, L.; Aumeunier, A.; Scott, C.L.; Mowat, A.; Cerovic, V.; Houston, S.A.; et al. Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal Immunol. 2014, 7, 101–113.
  114. Savage, A.K.; Liang, H.E.; Locksley, R.M. The Development of Steady-State Activation Hubs between Adult LTi ILC3s and Primed Macrophages in Small Intestine. J. Immunol. 2017, 199, 1912–1922.
  115. Zenewicz, L.A. IL-22 Binding Protein (IL-22BP) in the Regulation of IL-22 Biology. Front. Immunol. 2021, 12, 766586.
  116. Kotenko, S.V.; Izotova, L.S.; Mirochnitchenko, O.V.; Esterova, E.; Dickensheets, H.; Donnelly, R.P.; Pestka, S. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J. Immunol. 2001, 166, 7096–7103.
  117. Schmechel, S.; Konrad, A.; Diegelmann, J.; Glas, J.; Wetzke, M.; Paschos, E.; Lohse, P.; Goke, B.; Brand, S. Linking genetic susceptibility to Crohn’s disease with Th17 cell function: IL-22 serum levels are increased in Crohn’s disease and correlate with disease activity and IL23R genotype status. Inflamm. Bowel Dis. 2008, 14, 204–212.
  118. Wolk, K.; Witte, E.; Hoffmann, U.; Doecke, W.D.; Endesfelder, S.; Asadullah, K.; Sterry, W.; Volk, H.D.; Wittig, B.M.; Sabat, R. 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.
  119. Martin, J.C.; Beriou, G.; Heslan, M.; Bossard, C.; Jarry, A.; Abidi, A.; Hulin, P.; Menoret, S.; Thinard, R.; Anegon, I.; et al. IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis. Mucosal Immunol. 2016, 9, 539–549.
  120. Gui, X.; Li, J.; Ueno, A.; Iacucci, M.; Qian, J.; Ghosh, S. Histopathological Features of Inflammatory Bowel Disease are Associated With Different CD4+ T Cell Subsets in Colonic Mucosal Lamina Propria. J. Crohns Colitis 2018, 12, 1448–1458.
  121. Josefowicz, S.Z.; Lu, L.F.; Rudensky, A.Y. Regulatory T cells: Mechanisms of differentiation and function. Annu. Rev. Immunol. 2012, 30, 531–564.
  122. Itoh, M.; Takahashi, T.; Sakaguchi, N.; Kuniyasu, Y.; Shimizu, J.; Otsuka, F.; Sakaguchi, S. Thymus and autoimmunity: Production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 1999, 162, 5317–5326.
  123. 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.
  124. Hori, S.; Nomura, T.; Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299, 1057–1061.
  125. 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.
  126. Josefowicz, S.Z.; Rudensky, A. Control of regulatory T cell lineage commitment and maintenance. Immunity 2009, 30, 616–625.
  127. Abbas, A.K.; Benoist, C.; Bluestone, J.A.; Campbell, D.J.; Ghosh, S.; Hori, S.; Jiang, S.; Kuchroo, V.K.; Mathis, D.; Roncarolo, M.G.; et al. Regulatory T cells: Recommendations to simplify the nomenclature. Nat. Immunol. 2013, 14, 307–308.
  128. Sakaguchi, S.; Mikami, N.; Wing, J.B.; Tanaka, A.; Ichiyama, K.; Ohkura, N. Regulatory T Cells and Human Disease. Annu. Rev. Immunol. 2020, 38, 541–566.
  129. Hsieh, C.S.; Lee, H.M.; Lio, C.W. Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 2012, 12, 157–167.
  130. Lancaster, J.N.; Li, Y.; Ehrlich, L.I.R. Chemokine-Mediated Choreography of Thymocyte Development and Selection. Trends Immunol. 2018, 39, 86–98.
  131. Lancaster, J.N.; Thyagarajan, H.M.; Srinivasan, J.; Li, Y.; Hu, Z.; Ehrlich, L.I.R. Live-cell imaging reveals the relative contributions of antigen-presenting cell subsets to thymic central tolerance. Nat. Commun. 2019, 10, 2220.
  132. Caramalho, I.; Nunes-Cabaco, H.; Foxall, R.B.; Sousa, A.E. Regulatory T-Cell Development in the Human Thymus. Front. Immunol. 2015, 6, 395.
  133. Sakaguchi, S.; Yamaguchi, T.; Nomura, T.; Ono, M. Regulatory T cells and immune tolerance. Cell 2008, 133, 775–787.
  134. Takaba, H.; Takayanagi, H. The Mechanisms of T Cell Selection in the Thymus. Trends Immunol. 2017, 38, 805–816.
  135. Veenbergen, S.; Samsom, J.N. Maintenance of small intestinal and colonic tolerance by IL-10-producing regulatory T cell subsets. Curr. Opin. Immunol. 2012, 24, 269–276.
  136. Worbs, T.; Bode, U.; Yan, S.; Hoffmann, M.W.; Hintzen, G.; Bernhardt, G.; Forster, R.; Pabst, O. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J. Exp. Med. 2006, 203, 519–527.
  137. Hauet-Broere, F.; Unger, W.W.; Garssen, J.; Hoijer, M.A.; Kraal, G.; Samsom, J.N. Functional CD25− and CD25+ mucosal regulatory T cells are induced in gut-draining lymphoid tissue within 48 h after oral antigen application. Eur. J. Immunol. 2003, 33, 2801–2810.
  138. Davidson, T.S.; DiPaolo, R.J.; Andersson, J.; Shevach, E.M. Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J. Immunol. 2007, 178, 4022–4026.
  139. Kretschmer, K.; Apostolou, I.; Hawiger, D.; Khazaie, K.; Nussenzweig, M.C.; von Boehmer, H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 2005, 6, 1219–1227.
  140. Chen, W.; Jin, W.; Hardegen, N.; Lei, K.J.; Li, L.; Marinos, N.; McGrady, G.; Wahl, S.M. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 2003, 198, 1875–1886.
  141. Coombes, J.L.; Siddiqui, K.R.; Arancibia-Carcamo, C.V.; Hall, J.; Sun, C.M.; Belkaid, Y.; Powrie, F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J. Exp. Med. 2007, 204, 1757–1764.
  142. Mucida, D.; Park, Y.; Kim, G.; Turovskaya, O.; Scott, I.; Kronenberg, M.; Cheroutre, H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007, 317, 256–260.
  143. Wang, J.; Ioan-Facsinay, A.; van der Voort, E.I.; Huizinga, T.W.; Toes, R.E. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur. J. Immunol. 2007, 37, 129–138.
  144. Jacobse, J.; Li, J.; Rings, E.; Samsom, J.N.; Goettel, J.A. Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease. Front. Immunol. 2021, 12, 716499.
  145. Nelson, R.W.; Beisang, D.; Tubo, N.J.; Dileepan, T.; Wiesner, D.L.; Nielsen, K.; Wuthrich, M.; Klein, B.S.; Kotov, D.I.; Spanier, J.A.; et al. T cell receptor cross-reactivity between similar foreign and self peptides influences naive cell population size and autoimmunity. Immunity 2015, 42, 95–107.
  146. Tanoue, T.; Atarashi, K.; Honda, K. Development and maintenance of intestinal regulatory T cells. Nat. Rev. Immunol. 2016, 16, 295–309.
  147. Atarashi, K.; Tanoue, T.; Shima, T.; Imaoka, A.; Kuwahara, T.; Momose, Y.; Cheng, G.; Yamasaki, S.; Saito, T.; Ohba, Y.; et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011, 331, 337–341.
  148. Wing, J.B.; Tanaka, A.; Sakaguchi, S. Human FOXP3(+) Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer. Immunity 2019, 50, 302–316.
  149. Miyara, M.; Yoshioka, Y.; Kitoh, A.; Shima, T.; Wing, K.; Niwa, A.; Parizot, C.; Taflin, C.; Heike, T.; Valeyre, D.; et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009, 30, 899–911.
  150. Fisson, S.; Darrasse-Jeze, G.; Litvinova, E.; Septier, F.; Klatzmann, D.; Liblau, R.; Salomon, B.L. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J. Exp. Med. 2003, 198, 737–746.
  151. Asseman, C.; Mauze, S.; Leach, M.W.; Coffman, R.L.; Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 1999, 190, 995–1004.
  152. Wirtz, S.; Billmeier, U.; McHedlidze, T.; Blumberg, R.S.; Neurath, M.F. Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. Gastroenterology 2011, 141, 1875–1886.
  153. Nakamura, K.; Kitani, A.; Fuss, I.; Pedersen, A.; Harada, N.; Nawata, H.; Strober, W. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J. Immunol. 2004, 172, 834–842.
  154. Powrie, F.; Carlino, J.; Leach, M.W.; Mauze, S.; Coffman, R.L. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J. Exp. Med. 1996, 183, 2669–2674.
  155. Read, S.; Greenwald, R.; Izcue, A.; Robinson, N.; Mandelbrot, D.; Francisco, L.; Sharpe, A.H.; Powrie, F. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J. Immunol. 2006, 177, 4376–4383.
  156. Read, S.; Malmstrom, V.; Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J. Exp. Med. 2000, 192, 295–302.
  157. Burzyn, D.; Kuswanto, W.; Kolodin, D.; Shadrach, J.L.; Cerletti, M.; Jang, Y.; Sefik, E.; Tan, T.G.; Wagers, A.J.; Benoist, C.; et al. A special population of regulatory T cells potentiates muscle repair. Cell 2013, 155, 1282–1295.
  158. Schiering, C.; Krausgruber, T.; Chomka, A.; Frohlich, A.; Adelmann, K.; Wohlfert, E.A.; Pott, J.; Griseri, T.; Bollrath, J.; Hegazy, A.N.; et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 2014, 513, 564–568.
  159. Ohnmacht, C.; Park, J.H.; Cording, S.; Wing, J.B.; Atarashi, K.; Obata, Y.; Gaboriau-Routhiau, V.; Marques, R.; Dulauroy, S.; Fedoseeva, M.; et al. MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORgammat(+) T cells. Science 2015, 349, 989–993.
  160. Sefik, E.; Geva-Zatorsky, N.; Oh, S.; Konnikova, L.; Zemmour, D.; McGuire, A.M.; Burzyn, D.; Ortiz-Lopez, A.; Lobera, M.; Yang, J.; et al. MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORgamma(+) regulatory T cells. Science 2015, 349, 993–997.
  161. Kim, K.S.; Hong, S.W.; Han, D.; Yi, J.; Jung, J.; Yang, B.G.; Lee, J.Y.; Lee, M.; Surh, C.D. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 2016, 351, 858–863.
  162. Negi, S.; Saini, S.; Tandel, N.; Sahu, K.; Mishra, R.P.N.; Tyagi, R.K. Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice. Cells 2021, 10, 1847.
  163. Cassinotti, A.; Passamonti, F.; Segato, S. Cell Therapy in Inflammatory Bowel Disease. Pharmacol. Res. 2021, 163, 105247.
  164. Bacchetta, R.; Bigler, M.; Touraine, J.L.; Parkman, R.; Tovo, P.A.; Abrams, J.; de Waal Malefyt, R.; de Vries, J.E.; Roncarolo, M.G. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J. Exp. Med. 1994, 179, 493–502.
  165. He, J.; Tsai, L.M.; Leong, Y.A.; Hu, X.; Ma, C.S.; Chevalier, N.; Sun, X.; Vandenberg, K.; Rockman, S.; Ding, Y.; et al. Circulating precursor CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure. Immunity 2013, 39, 770–781.
  166. Ueno, H.; Banchereau, J.; Vinuesa, C.G. Pathophysiology of T follicular helper cells in humans and mice. Nat. Immunol. 2015, 16, 142–152.
  167. Moore, K.W.; de Waal Malefyt, R.; Coffman, R.L.; O’Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 2001, 19, 683–765.
  168. Jia, X.; Zhai, T.; Wang, B.; Yao, Q.; Li, Q.; Mu, K.; Zhang, J.A. Decreased number and impaired function of type 1 regulatory T cells in autoimmune diseases. J. Cell. Physiol. 2019, 234, 12442–12450.
  169. Sun, L.; Kong, R.; Li, H.; Wang, D. The Role of T Follicular Helper Cells and Interleukin-21 in the Pathogenesis of Inflammatory Bowel Disease. Gastroenterol. Res. Pract. 2021, 2021, 9621738.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Immunology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Raquel Gomez-Bris
,
Angela Saez
,
Beatriz Herrero-Fernandez
,
Cristina Rius
,
Hector Sanchez-Martinez
,
Jose M. Gonzalez-Granado
View Times: 671
Entry Collection: Gastrointestinal Disease
Revisions: 2 times (View History)
Update Date: 09 Feb 2023
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback