Date Published: October 3, 2013
Publisher: Public Library of Science
Author(s): John J. Worthington, Joanna E. Klementowicz, Sayema Rahman, Beata I. Czajkowska, Catherine Smedley, Herman Waldmann, Tim Sparwasser, Richard K. Grencis, Mark A. Travis, P’ng Loke.
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, TGFβ signalling in CD4+ T-cells is induced and that antibody-mediated inhibition of TGFβ function results in protection from infection. Mechanistically, we find that enhanced TGFβ signalling in CD4+ T-cells during infection involves expression of the TGFβ-activating integrin αvβ8 by dendritic cells (DCs), which we have previously shown is highly expressed by a subset of DCs in the intestine. Importantly, mice lacking integrin αvβ8 on DCs were completely resistant to chronic infection with T. muris, indicating an important functional role for integrin αvβ8-mediated TGFβ activation in promoting chronic infection. Protection from infection was dependent on CD4+ T-cells, but appeared independent of Foxp3+ Tregs. Instead, mice lacking integrin αvβ8 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.
Gastrointestinal parasitic helminth infections are extremely prevalent, affecting nearly one quarter of the world population. Development of chronic infection, defined as the presence of adult worms in the host, results in severe morbidity and health problems and has been heavily linked with promotion of poverty in affected regions . Current treatments involve the use of anti-helminthic drugs to kill the parasite, but this does not prevent rapid re-infection with worms and encounters problems with drug resistance. As infections with these intestinal parasites are usually chronic, it is likely that helminths are able to influence the immune system to prevent their expulsion. Therefore, understanding the cellular and molecular pathways that regulate the immune response during helminth infection will be crucial in identifying novel therapeutic targets for these poorly managed infections.
Infection with intestinal helminths can result in either expulsion or development of chronic infection, often depending on the type of CD4+ T-cell response generated. Generally, a chronic infection results when inappropriate Th1 cytokine production occurs, as opposed to an inability of CD4+ T-cells to mount a response. Expulsion of the parasite relies on the production of Th2 cytokines, in particular IL-13 which drives a combination of cytokine-mediated expulsion mechanisms such as increased epithelial cell turnover in the intestine , enhanced mucus production  and increased production of RELM-β . Our data now demonstrate an essential role for TGFβ and the TGFβ-activating integrin αvβ8 expressed by DCs in promoting chronic intestinal parasite infection, using T. muris, a mouse model of the prevalent human parasite Trichuris trichuria. We observed that TGFβ signalling in CD4+ T-cells is triggered early during T. muris infection, and antibody-mediated blockade of TGFβ function significantly protects mice from infection. Mechanistically, we find that enhanced TGFβ signalling in T-cells during infection occurs via expression of the TGFβ-activating integrin αvβ8 on DCs and that lack of this integrin on DCs completely protects mice from infection due to an enhanced protective Th2 response. We have therefore identified a novel pathway that regulates Th2 immune responses in the gut that could potentially be targeted to upregulate host protective immune responses during gut parasite infection.