Journal
GASTROENTEROLOGY
Volume 131, Issue 3, Pages 818-829Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2006.06.003
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Funding
- Biotechnology and Biological Sciences Research Council [BB/D524875/1] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
- BBSRC [BB/D524875/1] Funding Source: UKRI
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Background & Alms: Intestinal epithelial integrity and permeability is dependent on intercellular tight junction (TJ) complexes. How TJ integrity is regulated remains unclear, although, although phosphorylation and dephosphorylation of the integral membrane protein occludin is an important determinant of TJ formation and epithelial permeability. We have invested the role intestinal intraepithelial lymphocytes (iIELs) play in regulating epithelial permeability in response to infection. Methods: Recombinant strains of Toxoplasma gondii were used to assess intestinal epithelial barrier function and TJ integrity in mice with intact or depleted populations of iIELs. Alterations in epithelial permeability were correlated with TJ structure and the state of phosphorylation of occludin. iIEL in vivo reconstitution experiments were used to identify the iIELs required to maintain epithelial permeability and TJ integrity. Results: In the absence of gamma delta(+) iIELs, intestinal epithelial barrier function and the ability to restrict epithelial transmigration of Toxoplasma and the unrelated intracellular. bacterial pathogen Salmonella typhimurium was severely compromised. Leaky I epithelium in gamma delta(+) iLEL-deficient mice was associated with the absence of phosphorylation of serine residues of occludin and lack of claudin 3 and zona occludens-1 proteins in TJ complexes'. These deficiencies were attributable to the absence of a single subset of gamma delta T-cell receptor (TCR-V gamma 7(+)) iIELs that, after reconstitiuting gamma delta iIEL-deficient mice, restored epithelial barrier function and TJ complexes, resulting in increased. resistance to infection. Conclusions: These findings identify. a novel role for gamma delta(+) iIELs in maintaining TJ integrity and epithelial barrier function that have implications for understanding the pathogenesis of intestinal inflammatory diseases associated with disruption of TJ complexes.
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