Abstract
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.
Highlights
Gastrointestinal parasitic helminth infections are extremely prevalent, affecting nearly one quarter of the world population
Using a model parasite which infects mice, we find that a protein called transforming growth factor beta
When a protein called integrin avb8 is absent from dendritic cells of the immune system, transforming growth factor beta (TGFb) is no longer activated to signal to T-cells and mice are able to mount a protective immune response resulting in worm expulsion
Summary
Gastrointestinal parasitic helminth infections are extremely prevalent, affecting nearly one quarter of the world population. Current treatments involve the use of anti-helminthic drugs to kill the parasite, but this does not prevent rapid reinfection 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. A key cytokine that plays a multi-functional role in controlling immune responses is transforming growth factor beta (TGFb) [2]. Activation of TGFb is a key regulatory step in controlling the function of TGFb in the immune system
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