Memory CD8⁺T Cells Are Sufficient To Alleviate Impaired Host Resistance to Influenza A Virus Infection Caused by Neonatal Oxygen Supplementation

Abstract

Supplemental oxygen administered to preterm infants is an important clinical intervention, but it is associated with life-long changes in lung development and increased sensitivity to respiratory viral infections. The precise immunological changes caused by neonatal oxygen treatment remain poorly understood. We previously reported that adult mice exposed to supplemental oxygen as neonates display persistent pulmonary inflammation and enhanced mortality after a sublethal influenza A virus infection. These changes suggest that neonatal hyperoxia impairs the cytotoxic CD8 ؉ T cell response required to clear the virus. In this study, we show that although host resistance to several different strains of influenza A virus is reduced by neonatal hyperoxia, this treatment does not impair viral clearance, nor does it alter the magnitude of the virus-specific CD8 ؉ T cell response to primary infection. Moreover, memory T cells are sufficient to ameliorate the increased morbidity and mortality and alleviate the excessive lung damage observed in mice exposed to high oxygen levels as neonates, and we attribute this sufficiency principally to virus-specific memory CD8 ؉ T cells. Thus, we show that neonatal hyperoxia reduces host resistance to influenza virus infection without diminishing the function of cytotoxic T lymphocytes or the generation of virus-specific memory T cells and that CD8؉ memory T cells are sufficient to provide protection from negative consequences of this important life-saving intervention. Our findings suggest that vaccines that generate robust T cell memory may be efficacious at reducing the increased sensitivity to respiratory viral infections in people born prematurely.

Neonatal Hyperoxia Increases Sensitivity Of Adult Mice To Bleomycin-Induced Lung Fibrosis

“…It extends previous work showing that neonatal hyperoxia promotes fibrotic disease after infection with a sublethal dose of influenza A virus (21,22,33,34). Our findings suggest that individuals born prematurely and exposed to hyperoxia may be at increased risk for developing pulmonary fibrosis when their respiratory epithelium is damaged later in life.…”

“…Interestingly, the effects on neutrophil recruitment were more pronounced than when hyperoxia-exposed mice were infected with a sublethal dose of influenza A virus (HKx31, H3N2), wherein the increased percentage of neutrophils was similar to that of macrophages and lymphocytes (21). Subsequent studies revealed that neonatal hyperoxia did not impair the cytotoxic effects of CD8 1 T cells or memory T cells (33). Instead, neonatal hyperoxia reduced the epithelial expression of eosinophil-associated RNase (Ear)1, an antiviral RNase that inhibits viral replication, and this was associated with greater epithelial injury (34).…”

Neonatal hyperoxia alters the host response to influenza A virus infection in adult mice through multiple pathways

“…In addition, the work reported herein used only a single strain of influenza A virus. We have previously shown that host resistance of adult mice to several different strains of influenza virus, including HKx31 (H3N2), A/CA/04/09 (H1N1), and A/PR/8/34 (H1N1), was similarly reduced by exposure to neonatal hyperoxia (18). Therefore, while our findings do not address the role of MCP-1 or EC-SOD during infection with other strains of influenza virus (or in other strains of mice), identification of these pathways within this system improves our understanding of why individuals born preterm are at increased risk for respiratory disease later in life.…”

Neonatal Hyperoxia Stimulates the Expansion of Alveolar Epithelial Type II Cells

“…Although vascular changes were not observed at this age, microvessel pruning and rarefaction, cardiac hypertrophy, and reduced survival were observed by 1 year of age (22). Analogous to children born prematurely, young adult mice exposed to hyperoxia as neonates also exhibit an altered host response to influenza A virus infection (21,23,24). Because this model of neonatal hyperoxia phenotypically recapitulates human diseases attributed to prematurity, it may provide an opportunity to understand how a high-oxygen environment at birth permanently alters lung development.…”