Integrin alphavβ8 on human dendritic cells: a role in intestinal immune homeostasis

Abstract

Intestinal inflammatory disorders such as Crohn's disease contribute significantly to human mortality and morbidity. Although the cells and molecules involved in suppression of intestinal inflammation have been extensively documented in mouse models, a full understanding of how these work together in the healthy and diseased gut remains elusive. It is known, however, that tight regulation over TH17 cells and regulatory T cells (Treg) is required to maintain immune homeostasis in the intestine. Activation of the cytokine transforming growth factor-β (TGFβ), which is secreted by immune cells as an inactive complex, plays a crucial role in the induction of both Treg and TH17 cells. Recent work has shown that the alphavβ8 integrin is required for activation of TGFβ by murine dendritic cells (DC). Murine integrin alphavβ8 is thus of fundamental importance for Treg and TH17 induction and, subsequently, for intestinal immune homeostasis. However, little is known about the signals controlling the expression of integrin alphavβ8 on intestinal DC. Furthermore, whether this system is also important for regulation of the human system is entirely unknown.Here, expression of integrin alphavβ8 is shown on human intestinal CD1c+CD103+SIRPalpha+ DC and CD1c+CD103-SIRPalpha+ DC, but not on CD141+CD103+SIRPalpha- DC. Expression of integrin alphavβ8 is increased on DC from Crohn's disease patients, and on DC from non-IBD donors treated with LPS. Both LPS and a number of probiotic bacteria were also able to induce integrin alphavβ8 expression on human monocyte-derived DC (moDC), which suggested that the microbiota may play a role in the regulation of human integrin alphavβ8. Importantly, we have also shown that TGFβ is activated by integrin alphavβ8 on human moDC, and that integrin alphavβ8 promotes expression of forkhead box P3 (FOXP3) in naïve human T cells in vitro. Together, these data suggest that integrin alphavβ8-mediated activation of TGFβ by DC may play an important role in the regulation of human T cell responses in the human intestine, and that this pathway may be perturbed during intestinal inflammation.

Date of Award	31 Dec 2015
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mark Travis (Supervisor) & Richard Grencis (Supervisor)