Alpha versus beta: are we on the way to resolve the mystery as to which is the endogenous ligand for natural killer T cells?

Natural killer T (NKT) lymphocytes are a unique subset of cells that play a role in regulating the immune system. For the past decade, studies have focused upon attempts to define these cells and to determine the ligand(s) that are required for their development and peripheral activation. Many research groups have focused upon determining the mechanisms for activating or inhibiting NKT cells in an attempt to control immune-mediated disorders as well as infectious and malignant conditions by using different ligand structures. Alpha-anomeric glycolipids and phospholipids derived from mammalian, bacterial, protozoan and plant species have been suggested as potential ligands for these lymphocytes. Some of these ligands were structured in forms that can bind to CD1d molecules. The lack of alpha-anomeric glycosphingolipids in mammals and the modest effect of these ligands in human studies, along with recent data from animal models and humans on the NKT-dependent immunomodulatory effect of beta-glycosphingolipids, suggest that the beta-anomeric ligands have the potential to be the endogenous NKT ligand.