CD1 is a membrane protein with structural and functional similarities to the MHC molecules, restricting presentation of hydrophobic or lipid antigens to T cells or NK T cells. Unlike the MHC class I and II molecules, CD1 acts as a restricting factor in a nonpolymorphic manner. Altered lipid metabolisms occur in atherosclerosis, leading to accumulation of chemically modified lipids in the arterial wall where T lymphocytes and macrophages are accumulating. It is likely that the immune cells are exposed to the atherogenic lipid antigens and become activated. Preliminary data from our studies on cultured cells have shown that treatment with certain lipids can induce expression of CD1 in vascular smooth muscle cells. This raises the possibility that CD1-positive smooth muscle cells may behave like dendritic cells and present lipid antigens to CD1-restricted T cells during the development of atherosclerosis. The central hypothesis is that loading with atherogenic lipids can enhance expression of CD1 proteins in the progenitors of vascular smooth muscle cells (SMC), which in turn act as antigen presenting cells capable of presenting the lipid antigens to T or NK T cells.
Specific Aim 1 is to determine whether expression of CD1 is associated with differentiation of embryonic stem cells into vascular SMC;
Specific Aim 2 to determine whether cytokines or growth factors such as interleukin-4 and monocyte colony stimulating factor (M-CSF) can synergize with lipids to induce expression of CD1 in vascular SMC progenitors as well as mature adult SMC;
Specific Aim 3 to determine whether CD1 positive, lipid-loaded human SMC progenitors or ESC-derived SMC present CD1-restricted lipid antigens to T or NK T cells. Human embryonic stem cell lines will be used to generate SMC progenitors and produce stable cell lines which over-express CD1. Unique 3D culture system and T cell-human ESC/SMC co-cultures will be established. Fulfillment of the above objectives will provide novel mechanisms by which lipid antigens activate immune cells and cause inflammation in the arteries with atherosclerosis. ? ?
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