A tissue-scale strategy for sensing threats in barrier organs

Barrier organs rely on a limited set of pattern recognition receptors (PRRs) to detect diverse immunogenic challenges. How these organs assess threats and adjust immune responses to balance host protection with collateral damage remains unclear. Here, by characterizing the probability of detecting influenza infection across different cell types in the lung using single-molecule imaging and spatial transcriptomics, we discovered cell-type-specific probabilities of threat sensing: lowest in the epithelia and highest in the stroma. Such differential probabilities emerge from spatially graded expression of nucleic acid-sensing PRRs across lung tissue compartments, a strategy widely adopted by barrier organs. Selectively increasing the level of retinoic acid-inducible gene I (RIG-I) in lung epithelia in vivo exacerbates tissue damage upon non-infectious challenge, revealing the importance of dampening the sensitivity of barrier epithelia. Together, these results highlight a spatially tiered strategy to tolerate epithelia-restricted threats and yet enable progressively potent immune responses as threats invade deeper into the tissue.