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

Hayward, Sarah L.; Scharer, Christopher D.; Cartwright, Emily K.; Takamura, Shiki; Li, Zheng-Rong Tiger; Boss, Jeremy M.; Kohlmeier, Jacob E.

doi:10.1038/s41590-019-0584-x

Cited by 85 publications

(87 citation statements)

References 52 publications

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“…Therefore, great enthusiasm has recently centered on enhancing local CD8 + T RM responses as a promising vaccination strategy to control mucosal infections including influenza virus infection [12]. Much progress has been made recently regarding the cellular and molecular mechanisms regulating T RM cell development and maintenance [13, 14]. However, relatively less is known regarding the effects of aging in the development and/or function of T RM responses in the mucosal tissues following primary infection.…”

Section: Introductionmentioning

confidence: 99%

Tissue-resident CD8⁺T cells drive age-associated chronic lung sequelae following viral pneumonia

Sun

Goplen

2020

Preprint

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32Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome 33 coronavirus 2 (SARS-CoV2) infections, often cause severe viral pneumonia in aged individuals. 34Here, we report that influenza viral pneumonia leads to chronic non-resolving lung pathology 35 and exaggerated accumulation of CD8 + tissue-resident memory T cells (TRM) in the respiratory 36 tract of aged hosts. TRM accumulation relies on elevated TGF-b present in aged tissues. Further, 37we show that TRM isolated from aged lungs lack a subpopulation characterized by expression of 38 molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged 39 lungs were insufficient to provide heterologous protective immunity. Strikingly, the depletion of 40 CD8 + TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in 41 aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell 42 malfunction supports chronic lung inflammatory and fibrotic sequelae following viral pneumonia 43 in aged hosts. 44 45 46 47 48

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Section: Introductionmentioning

confidence: 99%

Tissue-resident CD8⁺T cells drive age-associated chronic lung sequelae following viral pneumonia

Sun

Goplen

2020

Preprint

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“…While local immune responses are important and, when combined with systemic responses, may provide optimal protection, it is fundamental to know how long they persist. Lung TRM have been shown to be short lived in mice, perhaps as a consequence of the high oxygen tension of the lung microenvironment 35,36 . However, experiments examining the persistence of influenza specific memory indicate that a dividing lung memory population may persist for many months if antigen is retained in the lung 7 .…”

Section: Discussionmentioning

confidence: 99%

Simultaneous aerosol and intra-muscular immunization with influenza vaccine induces powerful protective local T cell and systemic Ab immune responses in pigs

Martini

Paudyal

Chrun

et al. 2020

Preprint

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A vaccine providing both powerful antibody and cross-reactive T cell immune responses against influenza viruses would be beneficial for both humans and pigs. Here we evaluated intramuscular (IM), aerosol (Aer) and simultaneous immunization (SIM) by both routes in pigs, using the single cycle candidate influenza vaccine S-FLU. After prime and boost immunization pigs were challenged with H1N1pdm09 virus. IM immunized pigs generated high titer of neutralizing antibodies but poor T cell responses, while Aer induced powerful respiratory tract T cell responses, but a low titer of antibodies. SIM pigs combined high antibody titers and strong local T cell responses. SIM pigs showed the most complete suppression of virus shedding and the greatest improvement in pathology. We conclude that SIM regimes for immunization against respiratory pathogens warrant further study.

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“…For durable immunity, it is therefore important to understand what accounts for this short survival. Transcriptomic analysis revealed GCN2-dependent activation of the ISR as a unique signature in airway-resident T RM [111]. This appears to be a function of the nutrient-poor microenvironment of the airway but is reversible, since airway T RM cells cultured ex vivo in amino acid sufficient conditions are rescued.…”

Section: Bacterial Infectionmentioning

confidence: 98%

“…A challenge to the development of vaccines that impart cell-mediated immunity in the lung is the short lifespan of airway-resident memory T (T RM )-cells [111]. Unlike the long-lived T RM cells of other tissues, airway T RM cells are almost completely lost through apoptosis by 180 days following exposure to influenza or Sendai viruses [111]. For durable immunity, it is therefore important to understand what accounts for this short survival.…”

Section: Bacterial Infectionmentioning

confidence: 99%

The integrated stress response in pulmonary disease

et al. 2020

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The respiratory tract and its resident immune cells face daily exposure to stress, both from without and from within. Inhaled pathogens, including severe acute respiratory syndrome coronavirus 2, and toxins from pollution trigger a cellular defence system that reduces protein synthesis to minimise viral replication or the accumulation of misfolded proteins. Simultaneously, a gene expression programme enhances antioxidant and protein folding machineries in the lung. Four kinases (PERK, PKR, GCN2 and HRI) sense a diverse range of stresses to trigger this “integrated stress response”. Here we review recent advances identifying the integrated stress response as a critical pathway in the pathogenesis of pulmonary diseases, including pneumonias, thoracic malignancy, pulmonary fibrosis and pulmonary hypertension. Understanding the integrated stress response provides novel targets for the development of therapies.

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

Cited by 85 publications

References 52 publications

Tissue-resident CD8⁺T cells drive age-associated chronic lung sequelae following viral pneumonia

Tissue-resident CD8⁺T cells drive age-associated chronic lung sequelae following viral pneumonia

Simultaneous aerosol and intra-muscular immunization with influenza vaccine induces powerful protective local T cell and systemic Ab immune responses in pigs

The integrated stress response in pulmonary disease

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

Cited by 85 publications

References 52 publications

Tissue-resident CD8+T cells drive age-associated chronic lung sequelae following viral pneumonia

Tissue-resident CD8+T cells drive age-associated chronic lung sequelae following viral pneumonia

Simultaneous aerosol and intra-muscular immunization with influenza vaccine induces powerful protective local T cell and systemic Ab immune responses in pigs

The integrated stress response in pulmonary disease

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Product

Resources

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Tissue-resident CD8⁺T cells drive age-associated chronic lung sequelae following viral pneumonia

Tissue-resident CD8⁺T cells drive age-associated chronic lung sequelae following viral pneumonia