Hyperlipidemia alters Treg function through effects on Akt

Abstract

Abstract Hyperlipidemia is a common health condition in the transplant patient population. This condition causes end-stage heart disease in approximately 40% of all patients requiring a heart transplant, developing in 50% of heart transplant recipients after the first year and 95% of patients within 5 years of transplant. We have recently shown that hyperlipidemia promotes an aggressive rejection response that results in accelerated rejection of allogeneic heart transplants and resistance to tolerance induction. These results appear to be related to effects of hyperlipidemia on regulatory T cells (Tregs), including activation of Akt. Here we examined how activation of Akt might alter Treg function. Our data indicates that hyperlipidemia down-regulated regulators of Akt, allowing for increased Akt phosphorylation. Interestingly, hyperlipidemia preferentially affects the activation through phosphorylation of specific Akt isoforms and isoform specific targets. Akt isoforms activated because of hyperlipidemia in Tregs are not activated in CD4 effectors, suggesting a specific role in Tregs. Our data lead us to conclude that hyperlipidemia alters Treg function by altering specific Akt isoforms. These data may lead to new approaches that can be used to down or up-regulate Treg function.