TGF[beta]-activation by dendritic cells drives Th17 induction and intestinal contractility and augments the expulsion of the parasite Trichinella spiralis in mice

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 immunop...

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Bibliographic Details
Published in:PLoS pathogens 2019-04, Vol.15 (4)
Main Authors: Steel, Nicola, Faniyi, Aduragbemi A, Rahman, Sayema, Swietlik, Stefanie, Czajkowska, Beata I, Chan, Bethany T, Hardgrave, Alexander, Steel, Anthony, Sparwasser, Tim D, Assas, Mushref B, Grencis, Richard K, Travis, Mark A, Worthington, John J
Format: Article
Language:English
Subjects:
Analysis
Contractility (Biology)
Dendritic cells
Immune response
Inflammation
Integrins
Novels
Risk factors
T cells
Therapeutics
Transforming growth factors
Trichinosis
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Summary: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[beta] signalling responses in CD4+ T-cells. Mechanistically, enhanced TGF[beta] signalling in CD4+ T-cells is dependent on dendritic cell-mediated TGF[beta] activation which requires expression of the integrin [alpha]v[beta]8. Importantly, mice lacking integrin [alpha]v[beta]8 on DCs had a delayed ability to expel a T. spiralis infection, indicating an important functional role for integrin [alpha]v[beta]8-mediated TGF[beta] 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.
ISSN:1553-7366
1553-7374
DOI:10.1371/journal.ppat.1007657