Regulatory T cells (Treg) control both innate and adaptive immune responses and are essential to curb exacerbated inflammatory processes. Notably, Treg limit vascular endothelial injury and prevent pulmonary hypertension in human cohorts and animal models. Treg also appear dysfunctional in several metabolic diseases, including obesity and its diabetic complications. Interestingly, Treg were recently shown to mediate their survival through distinct metabolic pathways than effector T cells, relying more on fatty acid oxidation than glycolysis for energy generation. Treg take up externally derived fatty acids to support these high rates of fatty acid oxidation, but the involved molecules and pathways involved are not known. Thus understanding the interaction between Treg and lipids would provide novel insight into Treg biology. High-density lipoproteins have anti-inflammatory properties, which could be at least partially mediated by an effect of HDL on Treg. For example, intra-peritoneal injection of HDL into LDLR-/- mice increased splenic Treg counts. In addition, we recently showed in normocholesterolemic adults treated with statins that Treg frequency positively correlated with HDL cholesterol (HDL-c) levels, but not with those of LDL-c or triglycerides. Although these data strongly suggest that HDL-c promote Treg accrual, underlying mechanisms remain unclear. In particular, it is not clear whether HDL exert their effects on Treg homeostasis directly or indirectly. Our preliminary studies suggest the hypothesis that HDL interact directly with Treg, which enhances their survival through increased metabolic activity. Indeed, we showed that in vitro incubation of purified human Treg with HDL, but not LDL, significantly improved Treg survival. In contrast, HDL did not affect the survival of memory and nave CD4+ T cells. Supporting a direct effect of HDL on Treg, we found that Treg bind, and then internalize, HDL significantly more than their nave and memory counterparts. Significantly increased expression of the Scavenger Receptor class B (SR-BI/II) on Treg compared to other CD4+ T cell subsets appeared critical for this preferential uptake, as a blocking anti-SR-BI/II Ab abolished the HDL pro-survival effect. Mechanistically, we found that HDL uptake increased Treg metabolism, notably Treg mitochondrial activity, and that blocking fatty acid oxidation also abolished the HDL pro-survival effect. However, key gaps in knowledge remain. Notably, the pathways involved in HDL internalization by Treg and the molecular mechanisms by which HDL promote increased metabolic activity remain poorly understood. It is also not established whether HDL interactions may modify Treg functionality. Finally, we do not know which HDL component(s) is/are operational for Treg survival, although our preliminary data identified apoA-I as a prime candidate. In this proposal, we will address these gaps in knowledge through 2 Aims. In Sp.
Aim 1, we will (1) study the role of the SR-BI/II-mediated pathway in HDL internalization; (2) decipher the molecular mechanisms by which HDL promote Treg survival; and (3) determine whether HDL interactions modify Treg functionality. In Sp.
Aim 2, we will identify the HDL component(s) that is/are operational for Treg survival. We will use 2 complementary approaches, first testing the role of apoA-I in enhanced Treg survival, using reconstituted apoA-I HDL particles or conversely, apoA-I devoid particles, and then using proteomics to identify the HDL components that mediate their effect on Treg.

Public Health Relevance

Our preliminary studies suggest that up-regulation of High-density lipoprotein-cholesterol (HDL-C) increases survival of regulatory T cells (Treg) through direct signaling of Treg. Indeed, we showed that Treg frequency in statin-treated healthy individuals was significantly associated with HDL-C levels. Supporting a direct role for HDL, our Preliminary Data show that in vitro exposure of purified Treg to HDL significantly improved their survival, whereas HDL did not change memory and nave survival. A direct effect of HDL on Treg is consistent with the fact that Treg bind, and then internalize, HDL much more efficiently than their nave and memory counterparts. At completion, this project will have identified the principal mechanisms involved in HDL-mediated Treg survival. Deciphering these mechanisms has potentially broad immunological significance, due to the number of people using drugs that affect HDL levels.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Ramachandra, Lakshmi
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Cincinnati Children's Hospital Medical Center
United States
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Rueda, Cesar M; Rodríguez-Perea, Ana Lucia; Moreno-Fernandez, Maria et al. (2017) High density lipoproteins selectively promote the survival of human regulatory T cells. J Lipid Res 58:1514-1523