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 cytolyt...

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Bibliographic Details
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:	New York Nature Publishing Group US 01.03.2020 Nature Publishing Group
Subjects:	631/250/2152/1566/1571 631/250/347 Amino acid starvation Amino acids Animals Apoptosis Apoptosis - immunology Biomedical and Life Sciences Biomedicine 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 Immunology Infectious Diseases 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, 1529-2916
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Summary:	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. Kohlmeier and colleagues showed that the airway environment drove transcriptional and epigenetic changes that regulated the cytolytic functions of airway T RM cells and promoted their apoptosis due to amino acid starvation and activation of the integrated stress response.
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ISSN:	1529-2908 1529-2916 1529-2916
DOI:	10.1038/s41590-019-0584-x