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

• Published in: Nature immunology Vol. 21; no. 3; pp. 309 - 320
• Main Authors: Hayward, Sarah L, Scharer, Christopher D, Cartwright, Emily K, Takamura, Shiki, Li, Zheng-Rong Tiger, Boss, Jeremy M, Kohlmeier, Jacob E
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.03.2020; Nature Publishing Group US
• Subjects: Amino acid starvation; Amino acids; Animals; Apoptosis; Apoptosis - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell death; Cell lineage; Cell Survival - genetics; Cell Survival - immunology; Cell-mediated immunity; Cellular Microenvironment - genetics; Cellular Microenvironment - immunology; Cellular Reprogramming - genetics; Cellular Reprogramming - immunology; Cellular stress response; Effector cells; Epigenesis, Genetic - immunology; Epigenetics; Female; Immunologic Memory - genetics; Immunological memory; Lung - cytology; Lung - immunology; Lymphocytes; Lymphocytes T; Male; Memory cells; Mice; Mice, Inbred C57BL; Orthomyxoviridae Infections - genetics; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Respiratory diseases; Respiratory tract; Spleen; Stress response; Transcription
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-019-0584-x

Tissue-resident memory T cells (T 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 cells and promoted apoptosis due to amino acid starvation and activation of the integrated stress response. Comparison of airway T 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 cell lineage reprogramming. Importantly, activation of the integrated stress response was reversed in airway T cells placed in a nutrient-rich environment. Our data defined the genetic programs of distinct lung T cell populations and show that local environmental cues altered airway T cells to limit cytolytic function and promote cell death, which ultimately leads to fewer T cells in the lung.