Loss of the TGFß-Activating Integrin avß8 on Dendritic Cells Protects Mice from Chronic Intestinal Parasitic Infection via Control of Type

Chronic intestinal parasite infection is a major global health problem, but mechanisms that promote chronicity are poorly understood. Here we describe a novel cellular and molecular pathway involved in the development of chronic intestinal parasite infection. We show that, early during development of chronic infection with the murine intestinal parasite Trichuris muris, TGFb signalling in CD4+ T-cells is induced and that antibody-mediated inhibition of TGFb function results in protection from infection. Mechanistically, we find that enhanced TGFb signalling in CD4+ T-cells during infection involves expression of the TGFb-activating integrin avb8 by dendritic cells (DCs), which we have previously shown is highly expressed by a subset of DCs in the intestine. Importantly, mice lacking integrin avb8 on DCs were completely resistant to chronic infection with T. muris, indicating an important functional role for integrin avb8-mediated TGFb activation in promoting chronic infection. Protection from infection was dependent on CD4+ T-cells, but appeared independent of Foxp3+ Tregs. Instead, mice lacking integrin avb8 expression on DCs displayed an early increase in production of the protective type 2 cytokine IL-13 by CD4+ T-cells, and inhibition of this increase by crossing mice to IL-4 knockout mice restored parasite infection. Our results therefore provide novel insights into how type 2 immunity is controlled in the intestine, and may help contribute to development of new therapies aimed at promoting expulsion of gut helminths. Citation: Worthington JJ, Klementowicz JE, Rahman S, Czajkowska BI, Smedley C, et al. (2013) Loss of the TGFb-Activating Integrin avb8 on Dendritic Cells Protects Mice from Chronic Intestinal Parasitic Infection via Control of Type 2 Immunity. PLoS Pathog 9(10): e1003675. doi:10.1371/journal.ppat.1003675 Editor: P’ng Loke, New York University, United States of America Received May 10, 2013; Accepted August 16, 2013; Published October 3, 2013 Copyright: 2013 Worthington et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Financial support for this work was provided by the Medical Research Council and Biotechnology and Biological Sciences Research Council (to MAT). JEK was supported by a studentship from the Biological Sciences Research Council. The Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, is supported by core funding from the Wellcome Trust [grant number 088785/Z/09/Z]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work. ¤ Current address: Transplantation Research Lab, Department of Transplant Surgery, Parnassus Campus, University of California San Francisco, San Francisco, California, United States of America.