E-Thesis 3 views
Metabolic regulation of innate and adaptive immune responses of neonates / SEAN HOLM
Swansea University Author: SEAN HOLM
DOI (Published version): 10.23889/SUThesis.68215
Abstract
Immunometabolism is a burgeoning field of study providing novel insights into the mechanisms governing immune cell phenotype and function. However, most of this research has been conducted in adults resulting in a paucity of research concerning the metabolic features and requirements in early life in...
| Published: |
Swansea University, Wales, UK
2024
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| Institution: | Swansea University |
| Degree level: | Doctoral |
| Degree name: | Ph.D |
| Supervisor: | Thornton, C. A., and Jones N. |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa68215 |
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| Abstract: |
Immunometabolism is a burgeoning field of study providing novel insights into the mechanisms governing immune cell phenotype and function. However, most of this research has been conducted in adults resulting in a paucity of research concerning the metabolic features and requirements in early life including of human neonatal immune cells. This is despite the documented differences between adult and neonatal immune cell function. This thesis aims to address this by investigating the following questions: are the metabolic characteristics and requirements of neonatal immune cells different from adults and if so, do these unique characteristics and requirements explain the differences in immune cell phenotype and function seen in neonates? To explore these questions, immune cells, primarily naïve CD4+ T cells and neutrophils, were isolated from the peripheral blood of healthy adult donors and umbilical cord blood from term elective caesarean sections and experimentally interrogated ex vivo and in vitro. Functional assays, including bioenergetic flux, functional assays and phenotyping by flow cytometry were all used to provide insight into the metabolic and functional phenotype of adult and neonatal immune cells. For the first time, this thesis shows a distinctly enhanced glycolytic program on anti-CD3/28 activation in neonatal naïve CD4+ T cells accompanied by increased amino acid stabilised mTOR signalling highlighting an important role for metabolites in governing naïve CD4+ T cell activation. Furthermore, this thesis finds that failure to produce neutrophil extracellular traps by neonatal neutrophils is likely a result of reduced aerobic glycolytic capacity generating insufficient ATP to support this function. Together, these findings reveal the unique immunometabolic landscape of the neonate and begin to elucidate the mechanisms underpinning functional differences with adults, making a strong case for further investigation of neonatal immunometabolism, not only to provide novel therapeutic targets but also as a natural model of adult immune dysfunction. |
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| Item Description: |
A selection of content is redacted or is partially redacted from this thesis to protect sensitive and personal information. |
| Keywords: |
Immunology, Neonatal Immunology, metabolism, Immunometabolism |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
SURES |