The Effects of Hyperlipidemia on Regulatory T Cells
Hyde, Michael.
2021
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Thesis (Ph.D.)--Tufts University, 2021.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisor: Philip Hinds.
Committee: Xudong Li, and Caroline Genco.
Keyword: Biology.
Cardiovascular disease (CVD) is a leading cause of deaths worldwide. The World Health Organization (WHO) estimated 31% of all deaths globally are attributed to CVD ... read morein 2016. Hyperlipidemia is a major risk factor for cardiovascular disease and is found in more than 12% of adults in the United States, making this an extremely common comorbidity. Approximately 40% of patients who require a heart transplant are hyperlipidemic, and by 5 years after transplant 95% of heart transplant recipients are hyperlipidemic. We have recently shown that hyperlipidemia promotes an aggressive rejection response that results in accelerated rejection of allogeneic heart transplants and failure of regulatory T cell (Treg)-mediated tolerance induction. We also observed that hyperlipidemia induced the activation of Akt in Treg, suggesting that hyperlipidemia induces changes to Treg that impact function. Using live-cell metabolic assays, we show here that induction of hyperlipidemia modifies metabolism in Tregs but not conventional T cells as a result of activation of the serine/threonine kinase Akt2 (PKB). Expression of a constitutively activated form of Akt2 in murine T cells is sufficient to modify metabolism in Tregs and drive changes in Treg subsets, while induction of hyperlipidemia in mice lacking Akt2 did not alter Treg metabolism. This suggests a novel isoform-specific non-redundant effect of Akt on Treg phenotype and function. Activation of Akt2 leads to decreased levels of FoxO1 in the nucleus and reduced cell surface expression of its down-stream transcriptional targets PD-1 and Pten as determined by conventional and imaging flow cytometry. Akt2 activation was sufficient to drive production of inflammatory cytokines by Tregs. Our data suggest that effects on metabolism resulting from activation of Akt2 in Tregs leads to an increase in the production of inflammatory cytokines, a decrease in suppressive function and the promotion of a switch to an effector-like T cell phenotype. We also show that Tregs from aged mice are phenotypically similar to Tregs from hyperlipidemic mice. Tregs from aged mice have increased Akt phosphorylation, which led to alterations in Treg subsets and decreased FoxP3 and Bim expression levels. These data have direct implications for therapies designed to quell inflammation in hyperlipidemic and aging individuals and utilize Tregs for therapeutic benefit.read less - ID:
- 0c483z79r
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