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Metabolic regulation of innate and adaptive immune responses of neonates / SEAN HOLM

Swansea University Author: SEAN HOLM

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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...

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Published: Swansea University, Wales, UK 2024
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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first_indexed 2024-11-07T15:30:13Z
last_indexed 2024-11-07T15:30:13Z
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spelling v2 68215 2024-11-07 Metabolic regulation of innate and adaptive immune responses of neonates 49985e915eb47b06423a245be96e6ba3 SEAN HOLM SEAN HOLM true false 2024-11-07 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. E-Thesis Swansea University, Wales, UK Immunology, Neonatal Immunology, metabolism, Immunometabolism 24 10 2024 2024-10-24 10.23889/SUThesis.68215 A selection of content is redacted or is partially redacted from this thesis to protect sensitive and personal information. COLLEGE NANME COLLEGE CODE Swansea University Thornton, C. A., and Jones N. Doctoral Ph.D SURES SURES 2024-11-07T15:34:09.8834432 2024-11-07T15:26:19.6064919 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science SEAN HOLM 1 68215__32891__f15a1bc359c5464997d6a30e639f75a3.pdf 2023_Holm_S.final.68215.pdf 2024-11-07T15:29:46.9091046 Output 8003115 application/pdf E-Thesis – open access true Copyright: The Author, Sean Righardt Holm, 2023 true eng
title Metabolic regulation of innate and adaptive immune responses of neonates
spellingShingle Metabolic regulation of innate and adaptive immune responses of neonates
SEAN HOLM
title_short Metabolic regulation of innate and adaptive immune responses of neonates
title_full Metabolic regulation of innate and adaptive immune responses of neonates
title_fullStr Metabolic regulation of innate and adaptive immune responses of neonates
title_full_unstemmed Metabolic regulation of innate and adaptive immune responses of neonates
title_sort Metabolic regulation of innate and adaptive immune responses of neonates
author_id_str_mv 49985e915eb47b06423a245be96e6ba3
author_id_fullname_str_mv 49985e915eb47b06423a245be96e6ba3_***_SEAN HOLM
author SEAN HOLM
author2 SEAN HOLM
format E-Thesis
publishDate 2024
institution Swansea University
doi_str_mv 10.23889/SUThesis.68215
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description 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.
published_date 2024-10-24T15:34:08Z
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score 11.037056

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