Defining the roles of perforin, Fas/FasL, and tumour necrosis factor   in T cell induced mucosal damage in the mouse intestine

Merger, Michael; Viney, Joanne L.; Borojevic, Rajka; Steele‐Norwood, Darlene; Zhou, Pengfei; Clark, David A.; Riddell, Robert H.; Marić, R; Podack, Eckhard R.; Croitoru, Kenneth

doi:10.1136/gut.51.2.155

Cited by 93 publications

(103 citation statements)

References 41 publications

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“…In mice, acute T cell activation following i.p. injection of T cell-activating anti-CD3 mAb leads to severe small intestinal mucosal damage characterized by villus blunting and apoptosis of IEC (13). Therefore, i.p.…”

Section: Discussionmentioning

confidence: 99%

“…The model of anti-CD3 mAb i.p. injection was developed to study T cell driven inflammatory diseases such as IBD, celiac disease, or graft-versus-host disease (13). In mice, acute T cell activation following i.p.…”

Section: Discussionmentioning

confidence: 99%

“…injection with T cell activating monoclonal anti-CD3 Ab (anti-CD3 mAb) (13) and investigated the role of Nod2 on T cell activation, T cell-induced mucosal damage and recovery, specifically within the small intestine. Our results showed that acute T cell activation led to more severe crypt damage, increased crypt IEC apoptosis, and delayed epithelial regeneration in Nod2-deficient mice.…”

mentioning

confidence: 99%

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The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

Zanello

Goethel

Rouquier

et al. 2016

The Journal of Immunology

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Loss of function in the NOD2 gene is associated with a higher risk of developing Crohn’s disease (CD). CD is characterized by activation of T cells and activated T cells are involved in mucosal inflammation and mucosal damage. We found that acute T cell activation with anti-CD3 mAb induced stronger small intestinal mucosal damage in NOD2−/− mice compared with wild-type mice. This enhanced mucosal damage was characterized by loss of crypt architecture, increased epithelial cell apoptosis, delayed epithelial regeneration and an accumulation of inflammatory cytokines and Th17 cells in the small intestine. Partial microbiota depletion with antibiotics did not decrease mucosal damage 1 d after anti-CD3 mAb injection, but it significantly reduced crypt damage and inflammatory cytokine secretion in NOD2−/− mice 3 d after anti-CD3 mAb injection, indicating that microbial sensing by Nod2 was important to control mucosal damage and epithelial regeneration after anti-CD3 mAb injection. To determine which cells play a key role in microbial sensing and regulation of mucosal damage, we engineered mice carrying a cell-specific deletion of Nod2 in villin and Lyz2-expressing cells. T cell activation did not worsen crypt damage in mice carrying either cell-specific deletion of Nod2 compared with wild-type mice. However, increased numbers of apoptotic epithelial cells and higher expression of TNF-α and IL-22 were observed in mice carrying a deletion of Nod2 in Lyz2-expressing cells. Taken together, our results demonstrate that microbial sensing by Nod2 is an important mechanism to regulate small intestinal mucosal damage following acute T cell activation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

Zanello

Goethel

Rouquier

et al. 2016

The Journal of Immunology

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“…Despite the reduced numbers of T H cells in the LP of Hic1 DT mice and the dysregulated production of IL-17A by HIC1-deficient T H 17 cells, we failed to observe any significant differences in intestinal architecture between naive Hic1 fl/fl or Hic1 DT mice (Figure 6a, left panels). After induction of intestinal inflammation with intraperitoneal injection of a monoclonal antibody against CD3, [30][31][32] Hic1 DT mice displayed less intestinal inflammation compared with control Hic1 fl/fl mice (Figures 6a and b). Although we observed fewer CD4 þ T cells in the intestine of treated Hic1 DT mice (Figure 6c), we did observe an increase in the number of CD4 þ T cells in the LP of treated Hic1 DT mice compared with naive Hic1 DT mice (Figures 2a and b), further demonstrating that intestinal migration is not completely impaired in the absence of HIC1.…”

Section: Hic1 Regulates T Cell-mediated Inflammation In the Intestinementioning

confidence: 99%

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

et al. 2017

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“…T cells have been found to possess various potent antitumor effects through releasing cytotoxic effector molecules such as perforin or growth-suppressive cytokines IFN-γ and TNF-α [18][19][20][21] . However, the frequency of tumor-specific T cells could is generally too low and insufficient to interfere with progressive tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Superantigen-SEA gene modified tumor vaccine for hepatocellular carcinoma: Anin vitrostudy

Lu¹,

Sui²,

Li³

et al. 2004

WJG

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AIM:To construct an eukaryotic superantigen gene expression vector containing the recombinant gene of SEA and CD80 molecule transmembrane region (CD80TM), and to express staphylococcus enterotoxin A (SEA) on the membrane of hepatocellular carcinoma (HCC) cell to form a superantigen gene modified tumor vaccine for HCC. METHODS:SEA and linker-CD80TM gene were amplified through PCR from plasmid containing cDNA of SEA and CD80. Gene fragments were then subcloned into the multiple cloning sites of retroviral vector pLXSN. Recombinant plasmid was transferred into HepG2 cells mediated with lipofectamine, positive clones were selected in culture medium containing G418. RT-PCR and indirect immunofluorescence studies confirmed that SEA was expressed specifically on HCC cell membrane. INFγ-ELISPOT study demonstrated that SEA protein was expressed on the membrane of HCC cells. Cytotoxicity of HepG2-SEA primed CTLs (SEA-T) was analyzed by 51 Cr release assay. T cells cultured with rhIL-2 (IL-2-T) were used as control. RESULTS:Restriction digestion and sequence analyses confirmed the correctness of length, position and orientation of inserted fusion genes. SEA was expressed on the surface of HepG2 cells, HepG2-SEA had strong stimulating effect on production of HepG2 specific CTL (P<0.001). SEA-T had enhanced cytotoxicity to HepG2 cells (P<0.05). CONCLUSION:Tumor cell membrane expressed superantigen can be used to reinforce the immune effect of tumor cell vaccine for HCC, which provides a new method of the enhanced active immunotherapy for HCC.

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Defining the roles of perforin, Fas/FasL, and tumour necrosis factor in T cell induced mucosal damage in the mouse intestine

Cited by 93 publications

References 41 publications

The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell–Induced Enteropathy

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

Superantigen-SEA gene modified tumor vaccine for hepatocellular carcinoma: Anin vitrostudy

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