N-3 PUFAs & Antigen Presenting Cells Grant uri icon

abstract

  • N-3 polyunsaturated fatty acids (PU FAs) are recognized as bioactive immunosuppressive agents. A major limitation of using these fatty acids in the clinic as immunosuppressants is a poor understanding of their targets and molecular mechanisms. In vitro studies from our laboratory and others show that n-3 PUFAs suppress the function of antigen presenting cells (APCs) through the major histocompatibility complex (MHC) class I or MHC class II antigen presentation pathways. Mechanistically, we have found that n-3 PUFAs exert their effects by modifying the biophysical organization of the APC plasma membrane. However, the biological relevance of these findings has not been established in an animal model, which is the goal of this proposal. Our central hypothesis is that n-3 PUFA acyl chains disrupt nanometer scale MHC clustering on the plasma membrane surface, which in turn inhibits the ability of APCs to form a stable immunological synapse and activate T cells (Aim 1). The disruption in MHC clustering by n-3 PUFAs is driven by the formation of novel organizationally distinct nano-scale n-3 PUFA domains that serve to modify the size and distribution of sphingolipid-cholesterol-rich lipid rafts that compartmentalize MHC molecules inside or outside of rafts (Aim 2). To test our hypothesis, we will rely on a combination of biophysical microscopy methods and functional immunological assays to elucidate how n-3 PUFAs modify the organization of protein and lipid molecules on the micrometer to nanometer length scales to inhibit APC function. If our hypothesis is correct, we will establish for the first time that dietary n-3 PUFA acyl chains serve to disrupt nanoscale lipid and protein clustering and thereby suppress APC function. Given that APCs have a role in the removal of autoantigens and infectious agents, the studies proposed here will assist in the development of n-3 PUFAs as neutraceuticals for the treatment of inflammatory diseases, while minimizing their potential drawbacks.

date/time interval

  • May 2010 - September 2013