Evolution of T cell immunity in blood and tissues over childhood

PROJECT SUMMARY Immune system development during infancy and childhood sets the stage for a lifetime of protective immunity. Infants and children are known to be more susceptible to ubiquitous respiratory and mucosal pathogens for which adults have prior exposures. However, our recent experience in the COVID-19 pandemic, in which children were markedly less susceptible than adults to disease from infection with the novel respiratory virus SARS-CoV-2, indicate that children's immune systems can be highly effective to newly encountered pathogens. The diverse repertoire of naïve T cells, their ability to differentiate to tissue homing effector cells, which mediate pathogen clearance at infection sites, and the subsequent generation of long-lived memory T cells are critical events in immune responses that are not defined in children. Identifying the mechanisms by which T cells respond to antigenic challenges and establish immunological memory throughout infancy and childhood are essential for improving vaccines and immunotherapies to protect the next generation. My laboratory has been studying early life immunity in mouse models and novel human samples, including tissues from infant and pediatric organ donors, with a focus on how protective tissue resident memory T cells (TRM) become established in early life and mature over childhood. We pioneered the study of human tissue immunity in organ donor tissues, identifying that the majority of T cells across tissues in the body are TRM, which begin to form in early life in intestines and mature over age. We have identified fundamental and intrinsic differences in infant compared to adult T cells at the earliest stages in T cell activation and have investigated anti-viral immunity to SARS-CoV-2 in different pediatric cohorts. Our central hypothesis is that pediatric T cell responses are distinct due to intrinsic signaling mechanisms, the specific tissue environment, and the antigenic exposure history. In this study, we will build on our results, human samples, and cohorts to elucidate mechanisms for the distinct responses of pediatric T cells and their differentiation fate, maturation in tissues, and evolving response to vaccines. In aim 1, we will identify mechanisms for the distinct activation of pediatric naïve T cells, including how early events during T cell conjugate formation and cell division impact cell fate in early life and childhood for mouse and human T cells. In aim 2, we will elucidate TRM differentiation pathways and the role of the tissue in TRM maturation by high dimensional single cell profiling of human TRM in intestines and lungs across all ages of childhood, and use mouse models to address the role of persistence and tissue environment in TRM maturation. In aim 3, we will analyze vaccine-specific immune responses and evolution over childhood in established cohorts of children who previously had different clinical manifestations of SARS-CoV-2 infection, or were not infected. We will assess virus-specific T cell and antibody responses to the current COVID mRNA vaccines over time and age. Together, the proposed studies will comprehensively define immune system maturation over this critical and formative window of childhood.