TconTregApoAI · Apolipoprotein A-I and modulation of T cell functions
FP7 — People (Marie Curie Actions)
- Duration
- 2013-05-03 → 2015-05-02
- EU contribution
- €231,283
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
Apolipoprotein A-I and modulation of T cell functions
Cardiovascular disease (CVD) is a leading cause of mortality worldwide. Its underlying pathological process is atherosclerosis, a chronic inflammatory disease characterized by formation of a plaque in the intimal layer of the vessel wall. T cells present in atherosclerotic lesions produce proinflammatory mediators that promote plaque rupture and thrombosis. Several findings raise a possibility that apolipoprotein A-I (apoA-I), the most abundant HDL apolipoprotein, regulates T cell activity and function. Here I show that apoA-I and HDL can retard T-cell proliferation in serum-free medium and this is related to up-regulation to a key T-cell co-inhibitory molecule CTLA-4. Accordingly, T cells isolated from double knock-out (DKO) animals deficient in LDL receptor (LDLR) and apoA-I (LDLR-/-, apoA-I-/-) display hyper-proliferative potential and low expression of surface CTLA-4 upon CD3 stimulation in vitro. This is accordance with data showing that signaling in DKO T cells is affected by the absence of apoA-I. Motility of DKO T cells on ICAM-1 coated surface is greatly increased when compared to C57BL/6 T cells and provides a possible explanation for accumulation of T cells in lymph nodes of SKO and DKO animals. Finally, hyper-proliferation of DKO T cells could also be detected in homeostatic expansion model and in the absence of high-fat diet. This suggests that the lack of apoA-I during T cell development predisposes T cells to proliferate with higher rate.
Data: CORDIS, © European Union
Project objective
The pathogenesis of atherosclerosis involves inflammation and immune reactions. T cell responses contribute to local inflammation and growth of the atherosclerotic plaque. As intensified inflammatory activation may lead to local proteolysis, plaque rupture, and formation of a thrombus, studies of conventional and regulatory T cell functions during hypercholesterolemia are of outmost importance.Low levels of high-density lipoprotein (HDL) cholesterol are associated with inflammatory and immune disorders, including atherosclerosis. Although accumulating evidence suggests that HDL has anti-inflammatory properties, and functions as a part of the immune system, the mechanisms by which HDL inhibits atherosclerosis are not yet fully understood.Here, I propose to study the potential role of apoA-I in regulating the function of conventional and regulatory T cells. To this end, I will use hypercholesterolemic LDL receptor (LDLr) -/- and apoA-I-/- double knock-out (DKO) mice that develop severe atherosclerosis and display autoimmune phenotype, and, as a control, (LDLr) -/- single knock-out (SKO) mice fed atherogenic diet to study: 1) the role of apoA-I in regulating T cell motility, 2) the influence of apoAI on adhesion of T cells to antigen-presenting cells, 3) the effect of apoA-I on T-cell signaling molecules that regulate T cell motility and adhesion, 4) the relation between apoA-I and apoA-I-affected T-cell signaling molecules in vivo. These complementary approaches will allow me to investigate the role of apoA-I on regulating T cells functions, and will be indispensable to assess an impact of apoA-I-affected T-cell signaling molecules on atherosclerosis and autoimmune diseases.As conventional T cells critically modulate atherosclerosis by promoting inflammation, and regulatory T cells display atheroprotective properties, mechanistic insights into how apoA-I regulates T cell functions will advance our understanding of the immune processes involved in atherosclerosis.
Original text from CORDIS.
Participants
- THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGECoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union