Immunopathogenesis of IBD: Batf as a Key Driver of Disease Activity

Background: Inflammatory bowel diseases (IBDs) represent a group of chronic immune-mediated disorders that are influenced by a genetic predisposition and additional environmental triggers. Genome-wide association studies strongly implicate that a number of immune system-related genetic variations are critically contributing to the initiation and promotion of intestinal inflammation. Especially the identification of the strong association of a series of single nucleotide polymorphisms including interleukin (IL)-23R, CCR6, signal transducer and activator of transcription 3 (Stat3) and Stat4 with IBD susceptibility point at a critical involvement of T cells and especially of IL-17a-producing Th17 cells in the immune pathogenesis of IBD. In line with this hypothesis, a series of preclinical studies have unequivocally established that T cells are key drivers of immune-mediated colitis. Interestingly, especially Th17 cells were identified to be highly prevalent in inflamed IBD tissues, a finding that seems to be functionally relevant as genetic inactivation studies in the mouse resulted in almost complete suppression of colitis development. Key Messages: While targeting Th17 cell differentiation regulating transcription factors, as retinoic acid-related orphan receptor gamma t (RORγt) is effective in preventing murine colitis, one concern of drugs targeting RORγt in a clinical setting represents the large body of murine data unambiguously demonstrating that additional pathways within and outside the immune system are equally RORγt-dependent increasing the risk of undesirable side effects. The AP1 transcription factor Batf (B cell-activating transcription factor) appears to exclusively regulate pathways within lymphocytes. Importantly, Batf represents a central regulator of Th17 cell development and is strongly upregulated within IBD-affected tissues. Employing 2 acute colitis models, we demonstrate in this study that Batf-expressing T cells are critical drivers of T cell-mediated colitis while in contrast to Stat3 loss of Batf does not affect intestinal epithelial cell homeostasis ex vivo. Conclusions: Targeting Batf in IBD emerges as an attractive therapeutic approach disabling colitogenic T cell activities while sparing off-target effects in the intestinal epithelial cell compartment.

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Iron Overload Effects On Immune System Through The Cytokine Secretion By Macrophage

Blood ◽

10.1182/blood.v122.21.1047.1047 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1047-1047 ◽

Cited By ~ 2

Author(s):

Keiko Matsui ◽

Sachiko Ezoe ◽

Takafumi Yokota ◽

Tomohiko Ishibashi ◽

Kenji Oritani ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

Iron Overload ◽

Th17 Cell ◽

Th17 Cells ◽

Iron Dextran ◽

Immune Systems ◽

Treg Population

Abstract Iron is essential for almost all organisms. However, free iron can be cytotoxic at high concentration and iron excess can have adverse effects on variety of cells, tissue, and organ functions. In immune systems, many reports have shown the effects of iron, some of which are complex and controversial. Iron deficiency has been reported to be associated with increased susceptibility to infection, but iron overload caused by dietary excess abnormal hemolysis or inherited disorders is also associated with heightened susceptibility to infections. On the other hand, elevated ferritin levels, primarily related to RBC transfusions, have been reported to increase the risk of acute and chronic GVHD in patients received hematopoietic cell transplantation. Although this iron-related risk of GVHD may reflect the organ damage, such as liver, kidney, and pancreas, it also may be caused by imbalance in immune systems. To exaggerate the effects of iron overload on immune system, we established iron-loaded models in mice. First, as acute iron-loaded model, 10mg of iron dextran, which is even equal to 200U of RCC transfusion in human (define as 200U of iron dextran), was intraperitoneally injected into mice once a day for 18 days. In peripheral blood, T cell and B cell populations were decreased but monocyte/macrophage and neutrophil populations were increased as compared in control mice administered with dextran only. And notably, regulatory T cell (CD4+Foxp3+; Treg) population was significantly reduced in iron loaded mice than control mice (1.40% vs 0.58%). Next, as chronic iron-loaded model, 2U of iron dextran was injected once a week 45 times. Although significant difference was not observed in Treg population in PB, that in spleen was significantly high in iron-loaded mice as compared with that in control mice (3.2% vs 1.7%, p<0.05). From these data, we suspected that the excess of iron reduces Treg population in some organs, thereby effects on immune function. To clarify the mechanism of Treg-reduction by iron overload, we established an intermediate iron-loaded model, in which 50U of iron dextran was injected into mice once a week for 10 weeks, and following experiments were performed in this model. As previous examinations, Treg population in spleen was reduced in iron-loaded mice (0.86% vs 0.46%). T helper 17 (Th17) cells are recently described lymphocyte subset with common precursors with Treg but with opposing actions to Treg. The difference of Th17 cells could not be detected in spleen because of its too small population, the population of Th17 was increased in small intestine of iron-loaded mice (0.85% vs 1.51%). Treg and Th17 cells can be differentiated from naïve Th cells (CD4+CD62L+) with stimulation of specific cytokines (Treg; TGFβ, IFNγ, and IL4, Th17; TGFβ, IL-6, and IL-1β). We analyzed the direct effects of iron on Treg and Th17 cells during the in vitro differentiation from naïve T cells. Both in Treg and Th17 cell inductions, we could not detect significant differences between cells supplemented with iron dextran and those with dextran only. We also exaggerated the reactive oxide spesies (ROS) accumulated in induced T cell using RedCC1 staining. During the induction of Treg and Th17, although H2O2 supplement increased the ROS accumulation dose dependently, iron dextran-addition did not change the amount of ROS. Next, we analyzed the serum concentrations of cytokines in iron-loaded mice both in acute and intermediate models. IL-1β, and IL-23 levels were elevated in iron-loaded mice. These data suggested that iron overload reduces Treg cell population and increases Th17 cell population not directly, but through the cytokine secretion from environmental cells. So we evaluated the induction rates of Treg and Th17 cells from naïve T cells under co-culture with monocyte/macrophage. In this condition, Treg induction rate was significantly lower in iron dextran-supplemented cells (48.1% vs 35.3%), and Th17 induction was increased (8.4% vs 18.0%). Furthermore, mRNA expressions of IL-23 and IL-β in macrophages were increased with iron dextran-supplement in in vitro culture. These data suggest that iron overload changes the balance of Treg and Th17 cells through the proliferation and activation of macrophages, and thereby effects on the immunological condition of some disease, such as GVHD and autoimmune. Disclosures: No relevant conflicts of interest to declare.

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Heat shock transcription factor 2 inhibits intestinal epithelial cell apoptosis through the mitochondrial pathway in ulcerative colitis

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2020.04.103 ◽

2020 ◽

Vol 527 (1) ◽

pp. 173-179 ◽

Cited By ~ 2

Author(s):

Wen Wang ◽

Fengrui Zhang ◽

Xiaoyu Li ◽

Juan Luo ◽

Yang Sun ◽

...

Keyword(s):

Ulcerative Colitis ◽

Transcription Factor ◽

Heat Shock ◽

Epithelial Cell ◽

Cell Apoptosis ◽

Intestinal Epithelial Cell ◽

Mitochondrial Pathway ◽

Heat Shock Transcription Factor ◽

Intestinal Epithelial ◽

Epithelial Cell Apoptosis

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The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms21051673 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1673 ◽

Cited By ~ 3

Author(s):

Elodie Renaude ◽

Marie Kroemer ◽

Romain Loyon ◽

Delphine Binda ◽

Christophe Borg ◽

...

Keyword(s):

Dna Methylation ◽

T Cells ◽

Transcription Factor ◽

Tumor Microenvironment ◽

Th17 Cell ◽

Th17 Cells ◽

Epigenetic Modifications ◽

High Plasticity ◽

Th17 Cell Differentiation ◽

Promising Treatment

Th17 cells represent a subset of CD4+ T cells characterized by the master transcription factor RORγt and the production of IL-17. Epigenetic modifications such as post-translational histone modifications and DNA methylation play a key role in Th17 cell differentiation and high plasticity. Th17 cells are highly recruited in many types of cancer and can be associated with good or bad prognosis. Here, we will review the remodeling of the epigenome induced by the tumor microenvironment, which may explain Th17 cell predominance. We will also discuss the promising treatment perspectives of molecules targeting epigenetic enzymes to remodel a Th17-enriched tumor microenvironment.

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A subset of Cd8+regulatory T cells interacts with an intestinal epithelial cell complex formed by Cd1d and a CEA subfamily member

Gastroenterology ◽

10.1016/s0016-5085(03)80408-0 ◽

2003 ◽

Vol 124 (4) ◽

pp. A83

Author(s):

Matthieu Allez ◽

Jens Brinnes ◽

Ling Shao ◽

Iris Dotan ◽

Atsushi Nakazawa ◽

...

Keyword(s):

T Cells ◽

Epithelial Cell ◽

Regulatory T Cells ◽

Intestinal Epithelial Cell ◽

Cell Complex ◽

Intestinal Epithelial ◽

Subfamily Member

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Differentiation of a murine intestinal epithelial cell line (MIE) toward the M cell lineage

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00378.2007 ◽

2008 ◽

Vol 295 (2) ◽

pp. G273-G284 ◽

Cited By ~ 11

Author(s):

Takashi Kanaya ◽

Kohtaro Miyazawa ◽

Ikuro Takakura ◽

Wataru Itani ◽

Kouichi Watanabe ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Epithelial Cell ◽

Cell Line ◽

Intestinal Epithelial Cell ◽

Cell Lineage ◽

Epithelial Cell Line ◽

M Cells ◽

Intestinal Epithelial ◽

M Cell

M cells are a kind of intestinal epithelial cell in the follicle-associated epithelium of Peyer's patches. These cells can transport antigens and microorganisms into underlying lymphoid tissues. Despite the important role of M cells in mucosal immune responses, the origin and mechanisms of differentiation as well as cell death of M cells remain unclear. To clarify the mechanism of M cell differentiation, we established a novel murine intestinal epithelial cell line (MIE) from the C57BL/6 mouse. MIE cells grow rapidly and have a cobblestone morphology, which is a typical feature of intestinal epithelial cells. Additionally, they express cytokeratin, villin, cell-cell junctional proteins, and alkaline phosphatase activity and can form microvilli. Their expression of Musashi-1 antigen indicates that they may be close to intestinal stem cells or transit-amplifying cells. MIE cells are able to differentiate into the M cell lineage following coculture with intestinal lymphocytes, but not with Peyer's patch lymphocytes (PPL). However, PPL costimulated with anti-CD3/CD28 MAbs caused MIE cells to display typical features of M cells, such as transcytosis activity, the disorganization of microvilli, and the expression of M cell markers. This transcytosis activity of MIE cells was not induced by T cells isolated from PPL costimulated with the same MAbs and was reduced by the depletion of the T cell population from PPL. A mixture of T cells treated with MAbs and B cells both from PPL led MIE cells to differentiate into M cells. We report here that MIE cells have the potential ability to differentiate into M cells and that this differentiation required activated T cells and B cells.

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Human intestinal epithelial cell-induced CD8+ T cell activation is mediated through CD8 and the activation of CD8-associated p56lck.

Journal of Experimental Medicine ◽

10.1084/jem.182.4.1079 ◽

1995 ◽

Vol 182 (4) ◽

pp. 1079-1088 ◽

Cited By ~ 54

Author(s):

Y Li ◽

X Y Yio ◽

L Mayer

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Epithelial Cell ◽

Epithelial Cells ◽

T Cell Activation ◽

Cell Activation ◽

Intestinal Epithelial Cells ◽

T Cell Proliferation ◽

Intestinal Epithelial

The activation of CD8+ suppressor T cells by normal intestinal epithelial cells in antigen-specific or allogeneic mixed cell culture systems has significant implications for the regulation of mucosal immune responses. In this study, we found that the capacity of epithelial cells to induce CD8+ suppressor T cell activation appeared to be linked to the binding of CD8 molecules on the T cell surface. This appears to be mediated by a non-class I molecule expressed on the epithelial cell surface, which binds to CD8 and results in the activation of the CD8-associated src-like tyrosine kinase, p56lck. Epithelial cell-stimulated p56lck activation is an early event (in contrast to monocytes) and is essential for T cell activation, since proliferation could be completely abrogated by pretreatment of T cells with genestein or herbamycin, both of which are protein tyrosine kinase inhibitors. Pretreatment of T cells with anti-CD8 or of intestinal epithelial cells with an anti-epithelial cell mAb B9 inhibited p56lck activation and further confirmed that CD8 on the T cell and a CD8 ligand on the epithelial cell were involved in this T cell activation event. The specificity of this reaction was confirmed in experiments in which murine transfectants 3G4 and 3G8, expressing CD4 or CD8, respectively, were used. Coculture of 3G8 with epithelial cells but not with monocytes activated p56lck in this cell line, whereas p56lck was preferentially activated in 3G4 cells when monocytes were used as the stimulator cells. Although stimulation through CD8- and CD8-associated p56lck was important for epithelial cell-induced T cell activation, T cell proliferation could not be induced by cross-linking CD8 alone with monoclonal antibody anti-CD8. These data suggest that a second signal, possibly through the T cell antigen receptor since activation of the T cell receptor-associated kinase fyn was also seen, is required for epithelial cell-driven T cell proliferation.

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T‐Cell Protein Tyrosine Phosphatase Restricts Intestinal Epithelial Cell Expression of the Oncogene Annexin A4

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.610.2 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Moorthy Krishnan ◽

Maryam Aftabizadeh ◽

Hua Yu ◽

Declan F. McCole

Keyword(s):

T Cell ◽

Epithelial Cell ◽

Protein Tyrosine Phosphatase ◽

Intestinal Epithelial Cell ◽

Tyrosine Phosphatase ◽

Cell Protein ◽

Intestinal Epithelial ◽

Protein Tyrosine ◽

Annexin A4 ◽

Cell Expression

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HuR Plays a Positive Role to Strengthen the Signaling Pathways of CD4+ T Cell Activation and Th17 Cell Differentiation

Journal of Immunology Research ◽

10.1155/2021/9937243 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Shiguang Yu ◽

Morgan Tripod ◽

Ulus Atasoy ◽

Jing Chen

Keyword(s):

T Cells ◽

T Cell ◽

Signaling Pathways ◽

T Cell Activation ◽

Cd4 T Cells ◽

Th17 Cell ◽

Th17 Cells ◽

Cell Activation ◽

Cd4 T Cell ◽

Th17 Cell Differentiation

After antigen and/or different cytokine stimulation, CD4+ T cells activated and differentiated into distinct T helper (Th) cells via differential T cell signaling pathways. Transcriptional regulation of the activation and differentiation of naïve CD4+ T cells into distinct lineage Th cells such as Th17 cells has been fully studied. However, the role of RNA-binding protein HuR in the signaling pathways of their activation and differentiation has not been well characterized. Here, we used HuR conditional knockout (HuR KO) CD4+ T cells to study mechanisms underlying HuR regulation of T cell activation and differentiation through distinct signaling pathways. Our work showed that, mechanistically, HuR positively promoted CD3g expression by binding its mRNA and enhanced the expression of downstream adaptor Zap70 and Malt1 in activated CD4+ T cells. Compared to WT Th0 cells, HuR KO Th0 cells with reduced Bcl-2 expression are much more susceptible to apoptosis than WT Th0 cells. We also found that HuR stabilized IL-6Rα mRNA and promoted IL-6Rα protein expression, thereby upregulating its downstream phosphorylation of Jak1 and Stat3 and increased level of phosphorylation of IκBα to facilitate Th17 cell differentiation. However, knockout of HuR increased IL-22 production in Th17 cells, which was due to HuR deficiency in reducing IL-22 transcription repressor c-Maf expression. These results highlight the importance of HuR in TCR signaling and IL-6/IL-6R axis driving naïve CD4+ T cell activation and differentiation into Th17 cells.

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