MECHANISMS UNDERLYING NEONATAL CD8+ T CELL DEVELOPMENT AND RESPONSES

Neonatal infection is a major cause of morbidity and mortality worldwide. While adults generate robust immunity to most intracellular pathogens, neonates have an impaired ability to generate long-lasting immunity. As CD8+ T cells are essential for clearing intracellular pathogens, it is crucial to understand why these cells behave differently during infection in early life. We previously showed that neonatal CD8+ T cells rapidly become terminally differentiated and fail to form long-term memory following infection. However, the underlying basis for these age-related differences is unclear. In this thesis, experiments were designed to investigate how neonatal and adult CD8+ T cells behave differently and what underlying mechanisms contribute to these differences. We demonstrated that different aged CD8+ T cell progenitors have different gene expression profiles. Different aged progenitors also give rise to CD8+ T cells with distinct characteristics in the periphery when developed in the same thymic environment. Ectopic expression of the developmentally regulated protein Lin28b in adult CD8+ T cells granted them neonate-like traits. Our data indicate that different aged CD8+ T cells behave differently because they have different origins and Lin28b may regulate CD8+ T cell behaviors in early life. Neonatal CD8+ T cells also acquire a much more active metabolic profile compared to adult CD8+ T cells, which may contribute to their rapid contraction and poor memory formation following infection. Extrinsic differences between different aged animals were also studied by transferring adult CD8+ T cells into neonatal mice. Neonatal environment was able to modify adult CD8+ T cells to become phenotypically and functionally different. Neonatal-experienced adult CD8+ T cells proliferated more rapidly and formed insufficient memory. These findings suggest that in addition to cell-intrinsic factors, extrinsic factors may also contribute to age-related differences in CD8+ T cell behaviors. In summary, these findings advance our knowledge of neonatal CD8+ T cell responses and cast light on potential therapeutic targets early in life, such as Lin28b, mTOR and components of metabolic pathways. A more thorough understanding of neonatal immune responses is pivotal for combating diseases in neonates and improving their wellbeing