Abstract
To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses.
Highlights
To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat
Epithelial tissues regulate innate immune signaling in multiple ways: (i) receptor expression in intestinal epithelia is restricted to specific regions, cell types, or subcellular compartments[3,4]; (ii) cytokines produced during chronic inflammation[5,6] upregulate Toll-Like Receptor (TLR) expression and; (iii) epithelial cells become tolerant to repeated TLR stimulation[7]
Our results showed that responders contain significantly higher TLR2 mRNA counts when compared to non-responders (Fig. 4d)
Summary
To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. Epithelial tissues regulate innate immune signaling in multiple ways: (i) receptor expression in intestinal epithelia is restricted to specific regions, cell types, or subcellular compartments[3,4]; (ii) cytokines produced during chronic inflammation (e.g. irritable bowel syndrome, or cystic fibrosis)[5,6] upregulate TLR expression and; (iii) epithelial cells become tolerant to repeated TLR stimulation[7] These multiple layers of regulation highlight the dynamic nature of the epithelial innate immune system at both the tissue and single-cell levels, yet how these mechanisms are temporally coordinated to ensure quantitatively appropriate responses remains poorly understood. The role of epigenetic switches in shaping innate immune responses at the single-cell level has not been addressed
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