Environmental cues regulate epigenetic reprogramming of airway-resident memory CD8⁺ T cells

Tissue-resident memory T cells (T_RM cells) are critical for cellular immunity to respiratory pathogens and reside in both the airways and the interstitium. In the present study, we found that the airway environment drove transcriptional and epigenetic changes that specifically regulated the cytolytic functions of airway T_RM cells and promoted apoptosis due to amino acid starvation and activation of the integrated stress response. Comparison of airway T_RM cells and splenic effector-memory T cells transferred into the airways indicated that the environment was necessary to activate these pathways, but did not induce T_RM cell lineage reprogramming. Importantly, activation of the integrated stress response was reversed in airway T_RM cells placed in a nutrient-rich environment. Our data defined the genetic programs of distinct lung T_RM cell populations and show that local environmental cues altered airway T_RM cells to limit cytolytic function and promote cell death, which ultimately leads to fewer T_RM cells in the lung.