Tissue-resident memory T cells (TRM) in the lungs are pivotal for protection against repeated infection with respiratory viruses. However, the gradual loss of these cells over time and the associated decline in clinical protection represent a serious limit in the development of efficient T cell based vaccines against respiratory pathogens. Here, using an adenovirus expressing influenza nucleoprotein (AdNP), we show that CD8 TRM in the lungs can be maintained for at least 1 year post vaccination. Our results reveal that lung TRM continued to proliferate in situ 8 months after AdNP vaccination. Importantly, this required airway vaccination and antigen persistence in the lung, as non-respiratory routes of vaccination failed to support long-term lung TRM maintenance. In addition, parabiosis experiments show that in AdNP vaccinated mice, the lung TRM pool is also sustained by continual replenishment from circulating memory CD8 T cells that differentiate into lung TRM, a phenomenon not observed in influenza-infected parabiont partners. Concluding, these results demonstrate key requirements for long-lived cellular immunity to influenza virus, knowledge that could be utilized in future vaccine design.
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This project was supported by the Danish Research Council and ‘Fonden til Lægevidenskabens Fremme’ for grant support. IEMU is the recipient of a PhD scholarship from the Faculty of Health and Medical Sciences, University of Copenhagen. We would also like to acknowledge the support by NIH grants HL122559, HL138508, and Centers of Excellence in Influenza Research and Surveillance contract HHSN272201400004C (to J.E.K.), and Grant-in-Aid for Young Scientists (A) 24689043, Grant-in-Aid for Scientific Research (C) 16K08850 from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants from Takeda Science Foundation, Daiichi-Sankyo Foundation of Life Science, Uehara Memorial Foundation, and Kanae Foundation for Promotion of Medical Science (to S.T.). S.L.H. was supported by NIH grant F31 HL136101. We recognize contributions from the Children’s Healthcare of Atlanta and Emory University Pediatric Flow Cytometry Core for cell sorting and the NIH Tetramer Core Facility (contract HHSN272201300006C).
The authors declare no competing interests.
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Uddbäck, I., Cartwright, E.K., Schøller, A.S. et al. Long-term maintenance of lung resident memory T cells is mediated by persistent antigen. Mucosal Immunol 14, 92–99 (2021). https://doi.org/10.1038/s41385-020-0309-3
Nature Reviews Immunology (2021)