A type 1 immune-stromal cell network mediates disease tolerance and barrier protection against intestinal infection

Abstract

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 IFN{gamma} 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. IFN{gamma} 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. IFN{gamma} acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFN{gamma} 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 IFN{gamma} 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. HIGHLIGHTSO_LIType 1 immunity is required for disease tolerance to tissue-invasive infection. C_LIO_LIGut-resident CD8+ T cells produce IFN{gamma} in an antigen-independent, yet microbiota-dependent manner. C_LIO_LIIFN{gamma} signaling recruits neutrophils in a cell-extrinsic manner to limit helminth-induced tissue injury. C_LIO_LIDirect sensing of IFN{gamma} by intestinal stroma is essential to limit tissue damage and maintain gut motility during infection. C_LI