Development of Localized T Cell Immunity in Pediatric Respiratory Tract Infection

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7. PROJECT SUMMARY ABSTRACT Dr. Connors is a Pediatric Critical Care Physician Scientist investigating the generation and establishment of protective adaptive immune responses in infants and young children, particularly in the context of viral respiratory tract infections (VRTI). VRTI are ubiquitous in early life and commonly represent the first major challenge to the developing immune system. The majority of children clear infection without requiring medical attention, however severe disease from VRTI is the leading cause of respiratory failure necessitating mechanical ventilation during infancy. Importantly, associations between early life immune responses to infections and environmental exposures have been made to alterations in pulmonary function in later life. As immune responses in early life are formative for future protection from pathogens, aberrant responses in early life can have enduring repercussions. Differentiation of T cells to effector and memory subsets is required for viral clearance and establishment of protective immunity. Mouse models have demonstrated the importance of resident memory T cells (Trm) in mediating optimal protection. However neonatal mice T cells demonstrate transcriptionally distinct responses favoring the generation of terminally differentiated effector T cells over the establishment of Trm. Studies of human tissue have shown that T cells in tissue are predominately regulatory (Treg) in nature during infancy with few Trm. Importantly local T cell responses during VRTI are associated with disease severity in infants and children. The T cell subsets mediating protection during acute infection and the mechanisms leading to the establishment of long lived memory subsets remains uncharacterized in early life. Our central hypothesis is that protection from VRTI relies on the local adaptive immune response and aberrant immune responses during the formative window of infancy are associated with clinical severity. The aims of this proposal are 1) Determine pathways for T cell differentiation in early life and 2) Define the role of T cell subsets in VRTI induced Pediatric Acute Respiratory Distress Syndrome (PARDS). This career development award represents a crucial step in attaining the candidate’s long-term goal of transitioning to an independent researcher focused on translational studies of adaptive immune responses and critical illness in children. The academic, mentoring, training, and clinical opportunities afforded by the candidate’s current environment provide the perfect venues for successful completion of this project and for Dr. Connors to achieve his goal.