Abstract
TLR2 signaling is related to colitis and involved in regulation of innate immunity in the intestinal tract, but the mechanisms remain unclear. The aim of this study is to investigate how TLR2 affects differentiation of intraepithelial lymphocytes (IELs) and regulates the susceptibility of colitis. IELs were isolated from the small intestine and colon of mice, respectively. The IEL phenotype, activation, and apoptosis were examined using flow cytometry and RT-PCR. IL-15 expression and IEL location were detected through immunohistochemistry. The experimental colitis was induced by administration of dextran sulfate sodium (DSS). We found that the numbers of CD8αα +, CD8αβ +, and TCRγδ + IELs were significantly decreased in TLR2-deficient mice and the residual IELs displayed reduced activation and proliferation and increased apoptosis, accompanied with impaired IL-15 expression by intestinal epithelial cells (IECs). Further study showed that TLR2 signaling maintained the expression of IL-15 in IEC via NF-κB activation. Moreover, TLR2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis. Our results demonstrate that IECs contribute to the maintenance of IELs at least partly via TLR2-dependent IL-15 production, which provides a clue that may link IECs to innate immune protection of the host via IELs.
Highlights
Intestinal epithelial cells (IECs) maintain a fundamental immunoregulatory function that influences the development and homeostasis of mucosal immune cells
To investigate whether TLR2 signaling has an impact on the homeostasis of intraepithelial lymphocytes (IELs), we first examined the numbers of IELs in TLR2−/− mice
We found that TLR2-dependent signaling in IECs played an important role in development of IELs, and the signaling was essential in transcriptional activation of IL15 via NK-κB
Summary
Intestinal epithelial cells (IECs) maintain a fundamental immunoregulatory function that influences the development and homeostasis of mucosal immune cells. This single layer is home to an abundant population of intestinal intraepithelial lymphocytes (IELs). We and others previously reported that intestinal gut-derived cytokines are important for the homeostatic proliferation and survival of these IELs. For example, specific intestinal IL-7 overexpression (IL-7vill mice) significantly increased the number of type a IELs but did not have much effect on type b cell numbers [3]. Mice lacking the IL-15 system, including IL-15−/−, IL-15Rα−/−, and IL-15Rβ−/− mice, showed a severe reduction in CD8αα+TCRαβ+ and TCRγδ+ IELs [4, 5], combined with previous evidence showing that cytokines of the common γ-chain (γc) family (e.g., IL-7, IL15) are critical for development of IELs and depend on γc for cellular signaling
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