Natural killer T cells: Atherogenic Mechanisms and Therapeutic Targeting
Creators: name: Li, Yi
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: 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<sup>+</sup> 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<sup>+</sup> 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. <br> Adoptive transfer of CD4<sup>+</sup> iNKT cells isolated from wild type mice into Rag2<sup>-/-</sup>Apoe<sup>-/-</sup> and Rag2<sup>-/-</sup>γc<sup>-/-</sup>Apoe<sup>-/- </sup>mice developed bigger lesions compared to vehicle control mice. It indicated that CD4<sup>+</sup> iNKT cells can promote atherosclerosis independently of T, B and NK cells. Ja18<sup>-/-</sup>Apoe<sup>-/- </sup>mice, which are deficient only in iNKT cells, were adoptively transferred with CD4<sup>+</sup> 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<sup>-/-</sup>Apoe<sup>-/-</sup> 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. <br> NKT cells are activated via CD1d-assisted lipid antigen presentation by antigen presenting cells. DPPE-PEG<sub>350 </sub>(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-PEG<sub>350</sub> can therapeutically prevent NKT cell activation in atherosclerosis. DPPE-PEG<sub>350</sub> was administrated into Apoe<sup>-/-</sup> mice at the beginning of 8-week high fat diet. The lesion size decreased significantly in DPPE-PEG<sub>350</sub>-treated mice. Also, DPPE-PEG<sub>350</sub> treatment reduced necrotic core without affecting the content of smooth muscle cells and collagen. To investigate a potential of DPPE-PEG<sub>350</sub> in clinical translation, I designed an experiment where mice with established atherosclerosis were treated with DPPE-PEG<sub>350</sub>. Apoe<sup>-/-</sup> mice were fed a high fat diet for 6 weeks to establsih atherosclerosis and then treated with DPPE-PEG<sub>350</sub> for another 6 weeks while fed a high fat diet. DPPE-PEG<sub>350</sub> 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-PEG<sub>350 </sub>treatment is via blocking NKT cell activation, DPPE-PEG<sub>350</sub>-treated mice were challenged with α-GalCer (NKT cell agonist). Strikingly, α-GalCer failed to increase atherosclerosis in mice treated with DPPE-PEG<sub>350</sub> compared to mice that received α-GalCer alone, confirming that DPPE-PEG<sub>350</sub> treatment ameliorates atherosclerosis via NKT cell-dependent manner. <br> In conclusion, this study defines the mechanism by which CD4<sup>+</sup> iNKT cells promote atherosclerosis. It also shed light on therapeutic potential of DPPE-PEG<sub>350</sub> in targeting NKT cells in atherodclerosis and may lead to the finding of novel clinical treatment for atherosclerosis.