Control of intestinal Treg induction by integrin ?v?8 on dendritic cells
TM Fenton1, MJ Lehtinen2, MA Travis1
1Manchester Collaborative Centre for Inflammation Research and Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK. 2 DuPont Nutrition and Health, Kantvik, Finland
A balance of TH17 cells and regulatory T cells (Treg) is required to maintain immune homeostasis in the intestine. Activation of the cytokine TGF?, which is secreted as an inactive complex, plays a crucial role in the induction of both Treg and TH17 cells. We have previously shown expression of the integrin ?v?8 on dendritic cells is required for regulation of murine intestinal immune responses via TGFB activation. However, little is currently known about the mechanisms of TGF? activation in humans.
Here we have shown that ?v?8 is preferentially expressed on human CD1c+ intestinal dendritic cells (DC), and expression on these cells is highest in patients with active inflammatory bowel disease. We also found that integrin ?v?8 was upregulated on human DC by LPS stimulation, suggesting the enhanced expression of ?v?8 during inflammation could be driven by infiltrating microbiota.
Importantly, we have also shown that TGF? activation by ?v?8 on human DC promotes FOXP3 expression in naïve T cells ex vivo. Together, our data suggest that integrin ?v?8-mediated TGF? activation by human DC may play a crucial role in the regulation of T cell responses in the intestine, and that this pathway may be perturbed during intestinal inflammation.
Investigating the role of the TGF-?-activating integrin ?8 in inflammatory bowel disease
TGF-? is an important regulatory cytokine known to play a key role in the induction of T regulatory cells (Tregs), which are critical for the maintenance of immune homeostasis. TGF-? is secreted as a latent complex, requiring activation to be functional. Activation of TGF-? in the immune system is tightly regulated, one of the chief mechanisms being via the integrin ?v?8, which is expressed on immune cells such as dendritic cells (DCs) and Tregs. Mouse models have demonstrated a crucial role for ?v?8 in intestinal immune regulation, with lack of ?8 on DCs resulting in colitis, and ?8 knockout Tregs failing to suppress active inflammation in colitis models. However, the importance of these pathways in humans is completely unknown. Here, we examine the role of the TGF-?/?8 integrin pathway in human inflammatory bowel disease (IBD). Lamina propria mononuclear cells were isolated from inflamed and healthy patient intestinal biopsies and resection samples and integrin ?8 expression was measured. Real time PCR showed that ?8 expression was higher in intestinal tissue compared to peripheral immune cells, with immunohistochemistry revealing low ?8 protein expression in resection samples. However, there was a notable increase in ?8 expression in patients with intestinal inflammation, particularly in those with severe inflammation. Further examination of ?8 expression by flow cytometry showed that expression was upregulated on a number of lymphocyte and monocyte populations, including Tregs, during inflammation. Our current studies are dissecting the role of ?8 on different cell types in active inflammation in IBD.