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Apolipoprotein A-I and modulation of T cell functions

Final Report Summary - TCONTREGAPOAI (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.