A type 1 immune-stromal cell network mediates disease tolerance and barrier protection against intestinal infection
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Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here we demonstrate that rapid induction of IFNγ signaling coordinates a multi-cellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFNγ production is initiated by antigen-independent activation of lamina propria CD8 + T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion. IFNγ acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFNγ sensing also limited the expansion of smooth muscle actin-expressing cells to prevent pathological gut dysmotility. Importantly, this tissue-protective response had limited impact on parasite burden, indicating that IFNγ supports a disease tolerance defense strategy. Our results have important implications for managing the pathophysiological sequelae of post-infectious gut dysfunction and chronic inflammatory diseases associated with stromal remodelling.
HIGHLIGHTS
Type 1 immunity is required for disease tolerance to tissue-invasive infection.
Gut-resident CD8 + T cells produce IFNγ in an antigen-independent, yet microbiota-dependent manner.
IFNγ signaling recruits neutrophils in a cell-extrinsic manner to limit helminth-induced tissue injury.
Direct sensing of IFNγ by intestinal stroma is essential to limit tissue damage and maintain gut motility during infection.
