Role of Gastric Epithelial Cell-Derived Transforming Growth Factor β in Reduced CD4
            <sup>+</sup>
            T Cell Proliferation and Development of Regulatory T Cells during Helicobacter pylori Infection

Beswick, Ellen J.; Pinchuk, Iryna V.; Earley, Rachel; Schmitt, David A.; Reyes, Victor E.

doi:10.1128/iai.01146-10

Cited by 48 publications

(39 citation statements)

References 34 publications

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“…For GEC:T cells co-culture experiments naïve CD4 + T cells were isolated from peripheral blood as previously described (17). Briefly, heparinized venous blood samples were collected from healthy volunteers negative for H. pylori (IRB-approved protocol 06-122 at the University of Texas Medical Branch).…”

Section: Methodsmentioning

confidence: 99%

CagA-Dependent Downregulation of B7-H2 Expression on Gastric Mucosa and Inhibition of Th17 Responses during Helicobacter pylori Infection

Lina

Pinchuk

House

et al. 2013

The Journal of Immunology

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Gastric epithelial cells (GECs) are the primary target for Helicobacter pylori (H. pylori) infection and may act as antigen presenting cells (APC) regulating local T cell responses. We previously reported that H. pylori infection of GECs induces the expression of the T cell co-inhibitory molecule B7-H1 on GECs. This process contributes to the hyporesponsiveness of CD4+ effector T cells and accumulation of T regulatory cells. In the studies presented herein we investigated the impact of H. pylori cytotoxin CagA on the modulation of the expression of the T cell co-stimulator B7-H2 by GEC. B7-H2 is involved in promoting Th17 type responses. H. pylori infection downregulates B7-H2 expression by GECs in a CagA dependent manner. IFNγ, which is increased in the H. pylori infected gastric mucosa, synergizes with H. pylori in downregulating B7-H2 expression by GECs. CagA-mediated modulation of B7-H2 on GEC involves p70 S6 kinase phosphorylation. The CagA-dependent B7-H2 downregulation in GEC correlates with a decrease in Th17 type responses in vitro and in vivo. Further, CagA-dependent modulation of Th17 responses inversely correlated with the H. pylori colonization levels in vivo. Our data suggest that CagA contributes to the ability of H. pylori to evade Th17 mediated clearance by modulating expression of B7-H2 and, thus, to the establishment of the H. pylori chronic infection.

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Section: Methodsmentioning

confidence: 99%

CagA-Dependent Downregulation of B7-H2 Expression on Gastric Mucosa and Inhibition of Th17 Responses during Helicobacter pylori Infection

Lina

Pinchuk

House

et al. 2013

The Journal of Immunology

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“…Treg-epithelial interactions were previously described. For example, crosstalk between Tregs and the intestinal or retinal epithelium is an important determinant of both immune tolerance and Treg proliferation (40)(41)(42). Type II alveolar epithelial cells (AECs) can present antigen to naive Tcells through the Class II major histocompatibility complex (MHC), and induce the proliferation of Tregs, in part through a transforming growth factor (TGF)-b-dependent mechanism (43).…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Garibaldi

D’Alessio

Mock

et al. 2013

Am J Respir Cell Mol Biol

151

135

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Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1 2/2 mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1 2/2 mice received CD4 1 CD25 1 (Tregs) or CD4 1 CD252 Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1 2/2 mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1 2/2 mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1 2/2 mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.Keywords: acute lung injury; fibroproliferative ARDS; fibrocytes; regulatory T cells; lung injury resolution Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect 190,000 individuals in the United States each year, accounting for 75,000 deaths (1). The only treatment that improves outcomes involves a lung-protective strategy in patients on mechanical ventilation (2). Mortality from ALI/ARDS remains as high as 44% (3).ALI/ARDS is divided into an exudative phase marked by edema fluid, hyaline membrane formation, and neutrophilic infiltration, followed in some patients by a fibroproliferative phase (4). Fibroproliferation is part of the normal repair response, and is characterized by the intra-alveolar accumulation of fibroblasts and collagen deposition. If this process is ineffective or continues unabated, patients may develop fibrosis (5). Longer durations of ARDS correspond to increased lung collagen and fibrosis, and portend worse outcomes (6). Fibroproliferative changes on biopsy and computed tomography predict mortality (7,8). The determinants of prolonged fibroproliferation and factors that govern its resolution remain poorly understood.The fibroblast is a key cell ...

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“…Additionally, development and maintenance of this phenotype may further require IL-21, IL-23, or IL-1β, suggesting that there are several mechanisms that lead to the development of Th17 [9], [10]. We have previously shown that GECs express cytokines and receptors that influence the T cell response during H. pylori infection [11], [12]. In addition to GEC, we have also shown that CD90 + stromal cells (myofibroblasts and fibroblasts, MF) act as antigen presenting cells in the colon [13], [14].…”

Section: Introductionmentioning

confidence: 99%

Stromal Cells Induce Th17 during Helicobacter pylori Infection and in the Gastric Tumor Microenvironment

et al. 2013

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Gastric cancer is associated with chronic inflammation and Helicobacter pylori infection. Th17 cells are CD4+ T cells associated with infections and inflammation; but their role and mechanism of induction during carcinogenesis is not understood. Gastric myofibroblasts/fibroblasts (GMF) are abundant class II MHC expressing cells that act as novel antigen presenting cells. Here we have demonstrated the accumulation of Th17 in H. pylori-infected human tissues and in the gastric tumor microenvironment. GMF isolated from human gastric cancer and H. pylori infected tissues co-cultured with CD4+ T cells induced substantially higher levels of Th17 than GMF from normal tissues in an IL-6, TGF-β, and IL-21 dependent manner. Th17 required interaction with class II MHC on GMF for activation and proliferation. These studies suggest that Th17 are induced during both H. pylori infection and gastric cancer in the inflammatory milieu of gastric stroma and may be an important link between inflammation and carcinogenesis.

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Role of Gastric Epithelial Cell-Derived Transforming Growth Factor β in Reduced CD4 ⁺ T Cell Proliferation and Development of Regulatory T Cells during Helicobacter pylori Infection

Abstract: Gastric epithelial cells (GECs

Cited by 48 publications

References 34 publications

CagA-Dependent Downregulation of B7-H2 Expression on Gastric Mucosa and Inhibition of Th17 Responses during Helicobacter pylori Infection

CagA-Dependent Downregulation of B7-H2 Expression on Gastric Mucosa and Inhibition of Th17 Responses during Helicobacter pylori Infection

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Stromal Cells Induce Th17 during Helicobacter pylori Infection and in the Gastric Tumor Microenvironment

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Role of Gastric Epithelial Cell-Derived Transforming Growth Factor β in Reduced CD4 + T Cell Proliferation and Development of Regulatory T Cells during Helicobacter pylori Infection

Abstract: Gastric epithelial cells (GECs

Cited by 48 publications

References 34 publications

CagA-Dependent Downregulation of B7-H2 Expression on Gastric Mucosa and Inhibition of Th17 Responses during Helicobacter pylori Infection

CagA-Dependent Downregulation of B7-H2 Expression on Gastric Mucosa and Inhibition of Th17 Responses during Helicobacter pylori Infection

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Stromal Cells Induce Th17 during Helicobacter pylori Infection and in the Gastric Tumor Microenvironment

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Role of Gastric Epithelial Cell-Derived Transforming Growth Factor β in Reduced CD4 ⁺ T Cell Proliferation and Development of Regulatory T Cells during Helicobacter pylori Infection