Date of Completion
immunometabolism, Tregs, apolipoprotein, colitis, atherosclerosis, lipoprotein, tolerance, lipids, T cells, gut
Alison B Kohan
Field of Study
Doctor of Philosophy
The field of immunometabolism offers a potential pathway to regulate the immune system by altering the metabolic programs utilized by immune cells. While it is now known that there are different metabolic signatures of T cell lineages, a challenge in the field is determining how to manipulate these metabolic preferences in vivoto control immune activity in inflammatory disease.
Regulatory T cells (Tregs) are known for their immunosuppressive capacity. Treg metabolism is intimately linked with Treg stability and these cells rely mainly on fatty acids to fuel their function. Very little is known about how Tregs acquire extracellular lipids, which extracellular lipids are preferred, and the ultimate fate of those substrates in Tregs.
The canonical role of apolipoprotein C-III (apoC-III) is to inhibit the plasma clearance of lipoproteins by low-density lipoprotein receptor (LDLr). ApoC-III has tissue-specific roles. In liver apoC-III works to increase VLDL secretion, whereas intestinal apoC-III results in the secretion of smaller chylomicrons and modifies lipid absorption. It’s likely that apoC-III also plays a tissue-specific role in immune cells which express LDLr.
In this dissertation, we aimed to determine the role of apoC-III on Treg lipid metabolism and whether this can modulate disease susceptibility. In Aim 1, we identified the role of apoC-III on immune homeostasis. We found that apoC-III overexpression increases Tregs in the gut. We found that this phenotype persists during immune challenges and protects from colitis induction. In Aim 2 we identified how apoC-III modifies lipid metabolism in Tregs through inhibition of LDLr, its inhibitory target. Finally, in Aim 3 we found that excess exogenous apoC-III could protect from colitis. Furthermore, we found that excess apoC-III doesn’t manipulate Tregs through proliferation, suppression, or phenotypic changes suggesting that apoC-III causes accumulation of gut Tregs through another unknown mechanism.
This body of work identifies a novel role for apoC-III in Treg homeostasis through modification of cellular metabolism. This finding offers a potential target for therapeutic manipulation of Tregs. This work suggests a cautious approach should be taken towards targeting apoC-III for inhibition to reduce plasma lipids, which is a current approach for eliminating cardiovascular disease residual risk.
Rodia, Cayla Nicole, "The Role of Apolipoprotein C-III in Regulatory T cell Metabolism and Impact on Inflammatory Disease" (2019). Doctoral Dissertations. 2218.
Available for download on Wednesday, June 13, 2029