Investigating potential epigenetic mechanisms underpinning altered phenotypic responses of obese CD4\(^+\) T cells.

Gope, Atrayee (2024). Investigating potential epigenetic mechanisms underpinning altered phenotypic responses of obese CD4\(^+\) T cells. University of Birmingham. M.Sc.

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Abstract

Obesity, one of the leading causes of preventable death worldwide poses a huge burden on public health. It has a long-lasting negative effect on the immune system which can drive the development of chronic inflammatory disorders, contributing to high mortality rates. Essentially, a majority of obese people who lose weight go on to regain it and T lymphocytes play an important role in driving this weight re-gain. As we live longer and follow lifestyle that promotes obesity, it becomes increasingly important to understand the mechanisms that drive long-lasting immune dysregulation in obese individuals which persists even after weight loss. Research led by Prof. Claudio Mauro showed that obese CD4\(^+\) T lymphocytes preferentially differentiate into a pro-inflammatory effector memory like phenotype. Subsequent studies done in the lab found that this pro-inflammatory phenotype of obese CD4\(^+\) T cells is not rescued even after mice go on to lose weight after high-fat feeding. Subsequently, genome-wide DNA methylation studies identified 93 differentially methylated (70 hypomethylated and 23 hypermethylated) genes in the high-fat diet and high-fat recovery mice compared to mice on control (chow) diet. Out of the 70 hypomethylated genes, the following three were chosen for follow up studies - STK26, CDKN1C and IDH3G because of their relevance to autophagy, senescence, and TCA cycle, respectively. Our study made use of in vivo (murine) and in vitro (human) models of obesity and confirmed STK26 gene and protein upregulation as well as CDKN1C upregulation, while IDH3G gene or protein levels were not found to increase with obesity. Importantly, beside palmitic acid, stearic acid was also found to play a pro-inflammatory effect leading to altered obese CD4\(^+\) T cell responses. There was also seen a trend of autophagy induction with palmitic and stearic acid treatment, however, this would need to be repeated to establish statistical significance. Additionally, analysis of mRNA expression analysis by NanoString nCounter indicated altered senescence in the high-fat diet and high-fat recovery mice relative to chow diet. We thereby propose that STK26-induced autophagy and CDKN1C-induced senescence maintain pro-inflammatory effector memory CD4\(^+\) T cell population upon weight loss. Future studies involving analysis of autophagy markers by western blotting and investigation of CD4\(^+\) T lymphocytes, autophagy and senescence markers in STK26-knockout mice would provide deeper insights into the mechanisms by which autophagy, senescence, and the crosstalk between the two processes maintain CD4\(^+\) T cell inflammatory programs upon weight loss, which shall help develop therapeutic means/practices to ensure restoration of immune homeostasis upon weight loss and ensure long-term health.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):