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Regenerating murine CD8+ lung tissue resident memory T cells after targeted radiation exposure with mRNA-LNP

Regenerating murine CD8+ lung tissue resident memory T cells after targeted radiation exposure


Authors: Mariah Hassert, Pecia L. Pewe, Rui He, Mohammad Heidarian, Pornpoj Phruttiwanichakun, Stephanie van de Wall, Madison R. Mix, Aliasger K. Salem, Vladimir P. Badonivac, and John T. Harty

Abstract

Radiation exposure occurs during medical procedures, nuclear accidents, or spaceflight, making effective medical countermeasures a public health priority. Naive T cells are highly sensitive to radiation-induced depletion, although their numbers recover with time. Circulating memory CD8+ T cells are also depleted by radiation; however, their numbers do not recover. Critically, the impact of radiation exposure on tissue-resident memory T cells (TRM) remains unknown. Here, we found that sublethal thorax-targeted radiation resulted in the rapid and prolonged numerical decline of influenza A virus (IAV)–specific lung TRM in mice, but no decline in antigen-matched circulating memory T cells. Prolonged loss of lung TRM was associated with decreased heterosubtypic immunity. Importantly, boosting with IAV-epitope expressing pathogens that replicate in the lungs or peripheral tissues or with a peripherally administered mRNA vaccine regenerated lung TRM that was derived largely from circulating memory CD8+ T cells. Designing effective vaccination strategies to regenerate TRM will be important in combating the immunological effects of radiation exposure.


Fig. Radiation-induced loss of TRM in the lung results in compromised heterosubtypic immunity to influenza virus. (A) Experimental schematic to determine the effects of thorax-targeted radiation exposure on IAV susceptibility. Mice were administered P14 1 day prior to infection of half of the mice with X31-GP33. 30 days after X31 infection, half of the mice were exposed to 10 Gy of thorax-targeted radiation or treated similarly without radiation exposure. 30 DPR, mice were infected IN with 5LD50 of PR8-GP33. On day 4 after PR8 infection, mice were euthanized, and BAL and lung viral titers were measured via FFA. (B) Mice were weighed for 4 days following lethal PR8-GP33 challenge. (C) BAL PR8-GP33 titers on day 4. (D) Lung PR8-GP33 titers on day 4. ANOVA was utilized to determine statistically significant differences between groups. Data are pooled from two independent experiments (n = 9–13 mice per group). Statistical significance has been indicated within the figures with asterisks (*P = 0.03, **P = 0.002, *P = 0.0002, ****P < 0.0001).


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Keywords: CD8+; T cells; lipid nanoparticles; vaccination; Flex-M; Flex-S; LipidFlex


J Exp Med 2024, 221 (3),

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