Pediatric immune set points

Yale University, New Haven CT

Investigators

Abstract

PROJECT 1 – PEDIATRIC IMMUNE SET POINTS – SUMMARY Extensive person-to-person heterogeneity is a hallmark of the human immune system, both at homeostasis (“baseline” state) and in response to perturbations such as vaccines and infections. This immune variability can pose a barrier to the design of effective vaccines and therapeutics in the population. Independent of age, sex, and pre-existing antigen-specific immunity in adults, baseline immune status or “set point signatures” before vaccination, reflected in the frequency and transcriptional state of circulating immune cells, can predict and potentially determine the response to vaccination, infection, and disease activities in an antigen-agnostic manner. However, how baseline immune status is established and how it continues to evolve within an individual over time and in response to external perturbations remain poorly understood. During normal development from infancy to adolescence, children experience a wide range of environmental exposures, microbial challenges, and immunizations that influence the status of their immune system. These exposures together with intrinsic developmental progression are likely major determinants of baseline immune states in adulthood. However, our understanding of these processes is rudimentary at best, including how baseline immune set points are established early in life, and how the immune system shifts set point variables as a function of development and in response to external perturbations. Filling in these critical knowledge gaps will dramatically advance our understanding of human immune development, to ultimately enable better vaccines and rational modulation of immune states early in life to establish optimal developmental and health trajectories. The goal of the proposed research is to address these major knowledge gaps using cutting-edge systems immunology approaches, namely how baseline immune states develop from early childhood to adolescence (Aim P1.1), how they are shaped by inflammatory perturbations (Aim P1.2), and whether they predict future immune response outcomes (Aim P1.3). Together, the results of our proposed studies will provide unprecedented insights into the development and function of human immune set points. The impacts of the proposed work are also likely to extend beyond pediatric immunity and development, as the approaches, immune signatures, and hypotheses will deepen both our resource arsenals and fundamental understanding of the human immune system.