Lines Fellowship: Neonatal T cell responses to influenza virus

Rates of influenza virus infection and disease are greatest in young children. Neonates are immunologically immature, and shed virus at higher titers and for longer periods than adults. Children with high risk conditions (e.g. cardiovascular disease), and healthy children of ages 6 months to 2 years, are hospitalized at rates comparable to the elderly. In mouse infections, entry of T cells into neonatal lungs is defective. CD8 T cells enter neonatal lungs by day 10 post-infection, but not to high levels. CD4 T cell entry is delayed until 3 weeks of age. Interestingly, while CD4 T cells do reach adult levels in the interstitia, they are unable to cross the epithelial barrier into the alveoli. This is consistent with a report of interstitial inflammation in lungs of children after influenza-related death. The delayed entry of CD4 T cells corresponds delayed TNFa which may consequently lead to a delay in upregulation of integrins. In addition, IFNy is lacking in infected pups, so they may lack the IFNy-induced chemokines MIG and IP-10. The neonatal lung environment may not be providing responding T cells sufficient signals for entry and function. The goal of this project is to determine the mechanism(s) that result in prevention of T cells to enter the alveoli of infected pups. We will address the hypothesis: The neonatal T cell response to influenza is hindered by a lack of adequate signals for migration and activation. This hypothesis will be addressed by 2 aims. Aim 1: To determine if pup T cells are intrinsically defective in migration in response to influenza. We utilize adoptive transfer studies to determine if pup T cells are able to enter the adult lung environment in response to influenza infection. We will also examine chemokine receptor expression on T cells in the lung and draining lymph nodes of infected pups and adults. Aim 2: Determine if the neonatal lung environment supports migration of T cells in response to influenza. Using our adoptive transfer strategy we will determine if influenza-specific adult T cells can migrate into the alveolar spaces of neonatal mice. Moreover, we will examine adhesion molecule and chemokine expression in the neonatal lung before and after infection with influenza. These studies will be the first to examine T cell responses to live influenza infection in neonates. An understanding of the defects in this response will be valuable for development of better vaccination and treatment strategies for young children.