Monash University
20170106-Li-Thesis.pdf (14.21 MB)

Natural killer T cells: Atherogenic Mechanisms and Therapeutic Targeting

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posted on 2017-01-10, 04:00 authored by Yi Li
Atherosclerosis is a chronic inflammatory disease of medium and large-sized arteries. The immune system, including innate and adaptive components participates in development and progression of atherosclerosis. Immune cells, including dendritic cells, monocytes/macrophages, CD4/CD8+ T cells, B cells, natural killer cells and natural killer T cells present in both human and mouse atherosclerotic lesion. NKT cells have been shown to be pro-atherogenic in many studies and our group have identified that CD4+ iNKT cells are the NKT cell subset responsible for pro-atherogenic activity. However it is not clear how exactly these NKT cells exert their pro-atherogenic effect and whether NKT cells are therapeutically targeted to improve atherosclerosis.
       Adoptive transfer of CD4+ iNKT cells isolated from wild type mice into Rag2-/-Apoe-/- and Rag2-/-γc-/-Apoe-/- mice developed bigger lesions compared to vehicle control mice. It indicated that CD4+ iNKT cells can promote atherosclerosis independently of T, B and NK cells. Ja18-/-Apoe-/- mice, which are deficient only in iNKT cells, were adoptively transferred with CD4+ iNKT cells isolated from wild type or mice selectively deficient in interferon-γ, interleukin-4, interleukin-21, perforin or granzyme B. Compared to wild type and cytokine-deficient NKT cells, cytotoxin-deficient NKT cells failed to promote atherosclerosis in Ja18-/-Apoe-/- mice, suggesting that NKT cells utilise perforin and granzyme B in their atherogenic function. Moreover, smaller necrotic core area and less apoptotic cells were observed in mice that received cytotoxin-deficient NKT cells suggesting NKT cell-induced lesion cell death via cytotoxins.
       NKT cells are activated via CD1d-assisted lipid antigen presentation by antigen presenting cells. DPPE-PEG350 (NKT cell antagonist) is a chemical lipid antagonist which blocks NKT cell activation via competeing with lipid antigens in CD1d binding. Thus I investigated whether DPPE-PEG350 can therapeutically prevent NKT cell activation in atherosclerosis. DPPE-PEG350 was administrated into Apoe-/- mice at the beginning of 8-week high fat diet. The lesion size decreased significantly in DPPE-PEG350-treated mice. Also, DPPE-PEG350 treatment reduced necrotic core without affecting the content of smooth muscle cells and collagen. To investigate a potential of DPPE-PEG350 in clinical translation, I designed an experiment where mice with established atherosclerosis were treated with DPPE-PEG350. Apoe-/- mice were fed a high fat diet for 6 weeks to establsih atherosclerosis and then treated with DPPE-PEG350 for another 6 weeks while fed a high fat diet. DPPE-PEG350 treatment attenuated atherosclerosis without affecting smooth muscle cells and collagen and also reduced necrotic core and apoptotic cells. To test whether atherosclerosis reduced by DPPE-PEG350 treatment is via blocking NKT cell activation, DPPE-PEG350-treated mice were challenged with α-GalCer (NKT cell agonist). Strikingly, α-GalCer failed to increase atherosclerosis in mice treated with DPPE-PEG350 compared to mice that received α-GalCer alone, confirming that DPPE-PEG350 treatment ameliorates atherosclerosis via NKT cell-dependent manner.
       In conclusion, this study defines the mechanism by which CD4+ iNKT cells promote atherosclerosis. It also shed light on therapeutic potential of DPPE-PEG350 in targeting NKT cells in atherodclerosis and may lead to the finding of novel clinical treatment for atherosclerosis.


Principal supervisor

Ban-Hock Toh

Additional supervisor 1

Alex Bobik

Additional supervisor 2

Tin Soe Kyaw

Year of Award


Department, School or Centre

Medicine. Clinical Sciences at Monash Health

Campus location



Doctor of Philosophy

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Faculty of Medicine Nursing and Health Sciences

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