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Investigating the role of the intestinal barrier in regulation of immune homeostasis in the gut
[Thesis]. Manchester, UK: The University of Manchester; 2016.
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Abstract
The intestinal barrier represents a complex environment, composed of different physical barriers and immune cells, which act to prevent the entrance of potentially harmful enteric pathogens and to maintain gut tolerance to food antigens and commensal bacteria. Thus, cross-talk between the different components of the intestinal barrier such as the mucus layer, dendritic cells (DC) and intestinal intraepithelial lymphocytes (IELs) may be important in maintenance of gut homeostasis. This thesis investigates how different components of the intestinal barrier regulate immune responses in the gut. Thus, expression of the transmembrane receptor integrin αvβ8 on DCs is shown to be required for the development of a specific IEL subset marked by expression of CD4 and CD8αα, suggesting that intestinal DC play important roles in regulating the IEL compartment. Moreover, considering that intestinal DCs are likely in close contact with intestinal mucus, it was hypothesized that interactions between DCs and mucins, the predominant proteins that form the mucus layer, may modulate DC function. To test this hypothesis, intestinal mucin was purified and used to treat human monocyte-derived DCs. It was found that that expression of the chemokine IL-8 and co-stimulatory DC markers CD86 and CD83 are significantly upregulated on human DCs in the presence of intestinal mucins. Additionally, IL-8 produced by mucin-treated DCs is able to recruit neutrophil-like cells in transmigration assays. These effects were not due to mucin sample contaminants such as LPS, DNA or contaminant proteins. Instead, mucin glycans seem to be important for the induction of these effects on moDCs. Thus, in contrast to recent published results, intestinal mucins appear capable of inducing important pro-inflammatory functions in DC. To investigate whether mucins modulated DCs found in the intestinal environment, intestinal mucins were used to treat murine intestinal DCs, and gene changes explored using microarray analysis. It was found that, amongst several genes modulated in intestinal DC, up-regulation of the mucosal cytokine IL-22 was induced by intestinal mucin. Therefore, interactions between different components of the intestinal barrier might be crucial for maintaining gut homeostasis. Understanding how different components of the intestinal barrier system work together to maintain homoeostasis may identify pathways that can be targeted to restore this balance in inflammatory disorders such as inflammatory bowel disease.