Respiratory viruses, such as influenza and respiratory syncytial virus (RSV), constitute a major cause of illness and mortality in infants worldwide. The precise mechanisms underlying the diminished immune response to respiratory infection in infants remain unknown, and there are no specific strategies available to target respiratory immunity and improve clinical outcomes in infants. Most of our knowledge of the infant immune system is based on studies performed on peripheral blood;however it has become increasingly clear that mucosal sites such as the lung are important and distinct areas of T cell priming and protective immunity. Currently, it is not known whether the infant immune system can mobilize effector responses at peripheral sites of infection and/or generate pathogen-specific memory T cell responses which can populate peripheral tissue sites, such as the lung. We found that lung-resident T cells in infant mice are predominantly na?ve, contrasting the memory phenotype of lung resident T cells in adult mice. Influenza infection of infant mice results in reduced survival impaired viral clearance, severe lung pathology, and marked deficiencies in the production of T cell-derived effector cytokines in the lung compared to flu-infected adult mice. In the proposed study, we will investigate whether lung resident effector/memory T cell populations develop during viral infection and following vaccination in infant mice and humans, and investigate strategies to optimize antiviral immunity in the lung. Our central hypothesis is that infants exhibt dysregulated and ineffective immune responses to infections and vaccines for respiratory pathogens due to inadequate generation of effector/memory T cells in the lung, and that targeting lung responses is particularly important for improving infant immunity. Here, we will use mouse models of influenza infection and vaccination to examine the intrinsic capacity of infant na?ve T cells isolated from lung or spleen to develop into lung homing memory populations through adoptive transfer approaches and following intranasal or systemic vaccination. We will also determine the role of T cells, dendritic cells (DCs) and cytokines in immune protection and pathology during influenza infection, and whether manipulation of these parameters can improve infant respiratory immunity. Furthermore, we will extend our findings from mouse models, and examine the development of tissue-specific immunity through a novel analysis of endotracheal suctioning fluid in infants intubated due to respiratory failure from infection, and in human infants through the acquisition of tissue from organ donors that has been uniquely set up by my laboratory. Together, our investigation of infant lung immune responses in the steady state and in response to vaccination and infection, using mouse models and innovative human studies, will break new ground in our understanding of the infant immune system. Information gained from the proposed studies will allow for a more rational approach to future strategies for the prevention and treatment of respiratory illnesses in neonates and infants.
Infants experience disproportionate morbidity and mortality from seasonal respiratory viruses, and are more prone to severe illness and hospitalization, yet little is known about how the infant immune system responds to respiratory infection and to vaccines directed against respiratory pathogens. We have found that infant mice have fewer resident T cells in the lung and exhibit deficiencies in the mobilization and/or priming of effecto T cells in the lung. In the proposed research, we will characterize the lymphoid and lung immune response to influenza infection and vaccination in infant mice and humans, and determine strategies for therapeutic boosting of lung immunity in infants. The results obtained from these studies can lead to targeted therapies for boosting respiratory immunity in infants and improving the health of the youngest and most vulnerable of our population.
|Farber, Donna L; Yudanin, Naomi A; Restifo, Nicholas P (2014) Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol 14:24-35|
|Turner, Damian L; Gordon, Claire L; Farber, Donna L (2014) Tissue-resident T cells, in situ immunity and transplantation. Immunol Rev 258:150-66|