The Role of Macrophage Low Density Lipoprotein Receptor-Related Protein in the Activation of Invariant Natural Killer T cells

Abstract

Invariant natural killer T (iNKT) cells are unique group of lymphocytes that secrete copious amounts of immunoregulatory cytokines upon activation. This allows iNKT cells to modulate a wide range of mouse models that model human disorders such as multiple sclerosis, metastatic cancer, atherosclerosis, etc. The activation of iNKT cells relies on the presentation of glycolipids in the context of major histocompatibility molecule CD1d on antigen presenting cells (APCs). The mechanisms and cellular factors involved in the preparation of glycolipids for iNKT cell activation remain to be defined, yet expression of molecules involved in lipoprotein metabolism have been shown to play a role in iNKT cell activation. In the current study, we investigated the expression of low density lipoprotein receptor-related protein (LRP) and determined that macrophages (MFs) are the main cell type expressing LRP. Using a mouse model with a genetic deletion of LRP in MFs, we demonstrated that in vivo activation of iNKT cells with prototypical iNKT ligand, a-galactosyl-ceramide (aGC), leads to decreased serum levels of interleukin-4 (IL-4) and decreased production of IL-4 by iNKT cells. Using a fluorescently labeled glycolipid we show that LRP deletion increases the rate of glycolipid flux and through generation of bone marrow chimaeras determined that the decrease of the IL-4 response is iNKT cell extrinsic. Additionally, our studies revealed that in WT mice, challenge with aGC leads to a decrease in LRP levels that is iNKT cell and interferon-gamma dependent. These data demonstrate that LRP expression in MFs is critical for the activation of iNKT cells and that iNKT cell derived interferon-gamma can modulate LRP expression in WT MFs.