Date of Award
August 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical Engineering
First Advisor
Ramkumar Mathur
Abstract
This thesis explores the intricate relationship between mitochondrial oxidative stress and the function of FOXP3+ regulatory T cells (Tregs), highlighting their essential roles in the aging immune system and the development of age-related diseases. The study delves into how mitochondrial impairments within Tregs contribute to widespread inflammation leading to pathological aging. One key analysis shows that mitochondrial oxidative stress undermines Treg functionality, intensifying inflammatory responses and increasing frailty in older adults. This dysfunction is associated with elevated inflammatory markers and presents a potential target for therapeutic interventions aimed at restoring mitochondrial health to alleviate these impacts. Another significant discovery connects the dysfunction of CD4 Foxp3 Tregs in cerebrospinal fluid with the worsening of Alzheimer's pathologies. The study finds that mitochondrial deterioration within Tregs is crucial in regulating neuroinflammation, thereby affecting the progression of Alzheimer's disease. Enhancing mitochondrial function is identified as a possible approach to diminish inflammatory signals and the buildup of amyloid in the brain. A Foxp3-specific TFAM conditional knockout mouse model reveals that the absence of mitochondrial transcription factor A (TFAM) in Tregs leads to a shift in the CD4 T cell landscape toward more pathogenic profiles, characterized by increased cellular senescence, plasticity, and systemic inflammation. These findings highlight the potential of targeting mitochondrial function in Tregs as a novel therapeutic strategy to influence immune aging. The thesis underscores that boosting mitochondrial biogenesis or curtailing mitochondrial oxidative stress could stabilize Treg function, thus reducing inflammaging and its associated health risks. This research offers a thorough examination of the role of Tregs under mitochondrial oxidative stress, substantially enhancing our understanding of immune regulation in aging and its implications for treating age-related diseases. By outlining the links between mitochondrial dysfunction and immune regulation, this thesis enriches the field of geroscience, proposing viable interventions to improve health span and reduce the burdens faced by aging population.
Recommended Citation
Gill, Jappreet Singh, "Transcriptional Landscape Of FOXP3+ Regulatory T Cells Under Mitochondrial Oxidative Stress: Implications For Inflammaging" (2024). Theses and Dissertations. 6423.
https://commons.und.edu/theses/6423