The long term goal of this project is to understand a novel physiological mechanism that mediates activation of the immune system. Specifically, the ability of a special subset of immune cells termed invariant natural killer T cells (iNKT). Once activated these iNKT cells have the ability to secrete large amounts of cytokines that can activate the immune system within hours: as opposed to conventional T cells which can take 4-6 days. It is thought that due to the rapid response of iNKT cells they serve to alter disease progression. Activation of iNKT cells require the presentation of antigenic lipids in the context o molecule CD1d. This CD1d-dependent presentation appears to be altered in conditions of hyperlipidemia where increased levels of circulating lipids are present. Our laboratory has produced preliminary data showing that a receptor previously known to be involved in lipoprotein metabolism, the LDL receptor related protein (LRP), can play a role in iNKT cell activation. Therefore the hypothesis of this proposal is that LRP plays a role in glycolipid antige uptake and subsequent NKT cell activation. We propose two related but independent specific aims to test this hypothesis. In the first aim of this proposal we will examine the ability of LRP n APCs to make antigens available to iNKT cells. This will be done by using a mouse model with a genetic deletion of LRP in APCs. On the second aim, we will measure the ability of iNKT cells from these mice to function properly and whether deletion of LRP can lead to long term deficiencies in iNKT cell activation. In this aim we will also test the significant physiological relevance of impaired iNKT cell activation by testing the ability mice deficient in LRP to halt tumorigenesis in a mouse model of melanoma. Ultimately, the studies designed on this proposal will enhance our knowledge of normal physiological processes that can affect immune function.
Maintaining healthy immune system function is critical to combat a myriad of conditions such as autoimmunity, cancer and infection. In this proposal we describe a novel role of immune regulation to a molecule previously known to be involved in lipoprotein metabolism. Elucidation of this process is important because it will increase the understanding of physiological mechanisms that alter immune system function.
|Covarrubias, Roman; Wilhelm, Ashley J; Major, Amy S (2014) Specific deletion of LDL receptor-related protein on macrophages has skewed in vivo effects on cytokine production by invariant natural killer T cells. PLoS One 9:e102236|