Abstract
Helminths are highly prevalent metazoan parasites that infect over a billion of the world's population. Hosts have evolved numerous mechanisms to drive the expulsion of these parasites via Th2-driven immunity, but these responses must be tightly controlled to prevent equally devastating immunopathology. However, mechanisms that regulate this balance are still unclear. Here we show that the vigorous Th2 immune response driven by the small intestinal helminth Trichinella spiralis, is associated with increased TGF signalling responses in CD4+ T-cells. Mechanistically, enhanced TGF signalling in CD4+ T-cells is dependent on dendritic cell-mediated TGF activation which requires expression of the integrin v8. Importantly, mice lacking integrin v8 on DCs had a delayed ability to expel a T. spiralis infection, indicating an important functional role for integrin v8-mediated TGF activation in promoting parasite expulsion. In addition to maintaining regulatory T-cell responses, the CD4+ T-cell signalling of this pleiotropic cytokine induces a Th17 response which is crucial in promoting the intestinal muscle hypercontractility that drives worm expulsion. Collectively, these results provide novel insights into intestinal helminth expulsion beyond that of classical Th2 driven immunity, and highlight the importance of IL-17 in intestinal contraction which may aid therapeutics to numerous diseases of the intestine.
Author summary Infection with intestinal parasitic worms is a major global health problem. We have therefore evolved means to drive the expulsion of these worms (known as helminths), based on protective (type 2) immune responses. However, if these immune responses are not regulated they can result in more harm than good. One protein that can be key in controlling immune responses is transforming growth factor beta (TGF). Using a model helminth which infects mice, we found that TGF was indeed signalling to the immune cells which can initiate the type 2 response, but rather than increasing the regulation of these T-cells it was driving a different inflammatory immune response (termed Th17). Interestingly, this Th17 response was important in expelling the parasite, as mice lacking the ability to activate the TGF protein, lacked Th17 responses and the ability to contract intestinal muscles and flush out the parasite. Our findings therefore provide new insights into how helminths are expelled and identify potential molecular targets for the prevention of helminth infection which affects billions of the world's population in deprived communities.