Inchoate CD8+ T cell responses in neonatal mice permit influenza-induced persistent pulmonary dysfunction.
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-gamma-deficient mice demonstrated the importance of IFN-gamma 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.
You
Dahui
D
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Ripple
Michael
M
Balakrishna
Shrilatha
S
Troxclair
Dana
D
Sandquist
Dane
D
Ding
Liren
L
Ahlert
Terry A
TA
Cormier
Stephania A
SA
D019264:Adoptive Transfer; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D004195:Disease Models, Animal; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007371:Interferon-gamma; D008171:Lung Diseases / Q000276:immunology* / Q000473:pathology / Q000628:therapy* / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia; D011656:Pulmonary Emphysema; D012130:Respiratory Hypersensitivity; D016896:Treatment Outcome
D007371:Interferon-gamma