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  4. MECHANISMS UNDERLYING NEONATAL CD8+ T CELL DEVELOPMENT AND RESPONSES

MECHANISMS UNDERLYING NEONATAL CD8+ T CELL DEVELOPMENT AND RESPONSES

File(s)
Wang_cornellgrad_0058F_10633.pdf (8.92 MB)
Permanent Link(s)
https://doi.org/10.7298/X44T6GJ1
https://hdl.handle.net/1813/59007
Collections
Cornell Theses and Dissertations
Author
Wang, Jie
Abstract

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.

Date Issued
2017-12-30
Keywords
Immunology
Committee Chair
Rudd, Brian D.
Committee Member
Lee, Siu Sylvia
Flaminio, Maria Julia Bevilaqua Felippe
August, Avery
Degree Discipline
Immunology and Infectious Disease
Degree Name
Ph. D., Immunology and Infectious Disease
Degree Level
Doctor of Philosophy
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Rights URI
https://creativecommons.org/licenses/by-nc-nd/4.0/
Type
dissertation or thesis

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