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?? Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice.

ABSTRACT: Intraepithelial lymphocytes that express the ?? T-cell receptor (?? IELs) limit pathogen translocation across the intestinal epithelium by unknown mechanisms. We investigated whether ?? IEL migration and interaction with epithelial cells promote mucosal barrier maintenance during enteric infection.Salmonella typhimurium or Toxoplasma gondii were administered to knockout (KO) mice lacking either the T cell receptor ? chain (Tcrd) or CD103, or control TcrdEGFP C57BL/6 reporter mice. Intravital microscopy was used to visualize migration of green fluorescent protein (GFP)-tagged ?? T cells within the small intestinal mucosa of mice infected with DsRed-labeled S typhimurium. Mixed bone marrow chimeras were generated to assess the effects of ?? IEL migration on early pathogen invasion and chronic systemic infection.Morphometric analyses of intravital video microscopy data showed that ?? IELs rapidly localized to and remained near epithelial cells in direct contact with bacteria. Within 1 hour, greater numbers of T gondii or S typhimurium were present within mucosae of mice with migration-defective occludin KO ?? T cells, compared with controls. Pathogen invasion in Tcrd KO mice was quantitatively similar to that in mice with occludin-deficient ?? T cells, whereas invasion in CD103 KO mice, which have increased migration of ?? T cells into the lateral intercellular space, was reduced by 63%. Consistent with a role of ?? T-cell migration in early host defense, systemic salmonellosis developed more rapidly and with greater severity in mice with occludin-deficient ?? IELs, relative to those with wild-type or CD103 KO ?? IELs.In mice, intraepithelial migration to epithelial cells in contact with pathogens is essential to ?? IEL surveillance and immediate host defense. ?? IEL occludin is required for early surveillance that limits systemic disease.

SUBMITTER: Edelblum KL

PROVIDER: S-EPMC4685713 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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γδ Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice.

Edelblum Karen L KL Singh Gurminder G Odenwald Matthew A MA Lingaraju Amulya A El Bissati Kamal K McLeod Rima R Sperling Anne I AI Turner Jerrold R JR

Gastroenterology 20150304 7

<h4>Background & aims</h4>Intraepithelial lymphocytes that express the γδ T-cell receptor (γδ IELs) limit pathogen translocation across the intestinal epithelium by unknown mechanisms. We investigated whether γδ IEL migration and interaction with epithelial cells promote mucosal barrier maintenance during enteric infection.<h4>Methods</h4>Salmonella typhimurium or Toxoplasma gondii were administered to knockout (KO) mice lacking either the T cell receptor δ chain (Tcrd) or CD103, or control Tcrd ...[more]

PMID: 25747597

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Project description:BACKGROUND:Dysbiosis occurs in spondyloarthritis (SpA) and inflammatory bowel disease (IBD), which is subdivided into Crohn's disease (CD) and ulcerative colitis (UC). The immunologic consequences of alterations in microbiota, however, have not been defined. Intraepithelial lymphocytes (IELs) are T cells within the intestinal epithelium that are in close contact with bacteria and are likely to be modulated by changes in microbiota. We examined differences in human gut-associated bacteria and tested correlation with functional changes in IELs in patients with axial SpA (axSpA), CD, or UC, and in controls. METHODS:We conducted a case-control study to evaluate IELs from pinch biopsies of grossly normal colonic tissue from subjects with biopsy-proven CD or UC, axSpA fulfilling Assessment of SpondyloArthritis International Society (ASAS) criteria and from controls during endoscopy. IELs were harvested and characterized by flow cytometry for cell surface markers. Secreted cytokines were measured by ELISA. Microbiome analysis was by 16S rRNA gene sequencing from rectal swabs. Statistical analyses were performed with the Kruskal-Wallis and Spearman's rank tests. RESULTS:The total number of IELs was significantly decreased in subjects with axSpA compared to those with IBD and controls, likely due to a decrease in TCR?+ IELs. We found strong, significant negative correlation between peripheral lymphocyte count and IEL number. IELs secreted significantly increased IL-1? in patients with UC, significantly increased IL-17A and IFN-? in patients with CD, and significantly increased TNF-? in patients with CD and axSpA as compared to other cohorts. For each disease subtype, IELs and IEL-produced cytokines were positively and negatively correlated with the relative abundance of multiple bacterial taxa. CONCLUSIONS:Our data indicate differences in IEL function among subjects with axSpA, CD, and UC compared to healthy controls. We propose that the observed correlation between altered microbiota and IEL function in these populations are relevant to the pathogenesis of axSpA and IBD, and discuss possible mechanisms. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02389075 . Registered on 17 March 2015.

Dataset Information

?? Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice.

Publications

γδ Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice.

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