Inchoate CD8+ T Cell Responses in Neonatal Mice Permit Influenza-Induced Persistent Pulmonary Dysfunction

Abstract

Influenza infection remains a significant cause of pulmonary morbidity and mortality worldwide, with the highest hospitalization and mortality rates occurring in infants and elder adults. The mechanisms inducing this considerable morbidity and mortality are largely unknown. To address this question, we established a neonatal mouse model of influenza infection to test the hypothesis that the immaturity of the neonatal immune system is responsible for the severe pulmonary disease observed in infants. Seven-day-old mice were infected with influenza A virus (H1N1) and allowed to mature. As adults, these mice showed enhanced airway hyperreactivity, chronic pulmonary inflammation, and diffuse emphysematous-type lesions in the lungs. The adaptive immune responses of the neonates were much weaker than those of adults. This insufficiency appeared to be in both magnitude and functionality and was most apparent in the CD8+ T cell population. To determine the role of neonatal CD8+ T cells in disease outcome, adult, naive CD8+ T cells were adoptively transferred into neonates before infection. Neonatal mice receiving the adult CD8+ T cells had significantly lower pulmonary viral titers and greatly improved pulmonary function as adults (airway resistance similar to SHAM). Additional adoptive transfer studies using adult CD8+ T cells from IFN-γ-deficient mice demonstrated the importance of IFN-γ from CD8+ T cells in controlling the infection and in determining disease outcome. Our data indicate that neonates are more vulnerable to severe infections due to immaturity of their immune system and emphasize the importance of vaccination in infants.

CD4+T Cells Are Not Essential for Control of Early AcuteCryptosporidium parvumInfection in Neonatal Mice

“…The transfer of adult T cells into newborn mice has increased resistance to microbial pathogens such as influenza virus, suggesting that resident neonatal T cells are less efficiently activated (39). Neonatal mice or goats may compensate for impaired adaptive immune responses by developing more potent innate immune responses than adults, and this may result from increased inflammatory activation through Toll-like receptors (TLRs) (28,29,38).…”

Novel H1N1 influenza in neonates: from mild to fatal disease

“…4 Recent animal as well as human infant studies suggest that failure to develop a cytotoxic T lymphocyte response is a possible cause of the high rate of infant morbidity and mortality caused by respiratory viruses. 3,5 Among the 39 pediatric deaths associated with H1N1 novel influenza infection in the United States, 67% had at least one highrisk medical condition. 2 Our first patient possibly belonged to the high-risk group because of the congenital abnormality of the upper respiratory tract as well as the prolonged mechanical ventilation.…”

“…2 Neonates, because of the immaturity of their immune system, could represent a high-risk group. 3 However, reports on infection with H1N1 influenza in neonates are very scarce.…”

Regulatory T Cells Are Critical for Clearing Influenza A Virus in Neonatal Mice

“…Yearly influenza epidemics are particularly difficult for populations known to have deficiencies in immune function such as the very young and elderly. Very few studies have examined the neonatal immune response to IAV (21,47), but it has been appreciated for some time that neonatal T-cell responses to antigen are frequently biased toward T helper 2 (Th2) cytokines (1,30).…”