Natural Killer T (NKT) cells are a unique T cell population characterized by features of both the innate and adaptive immune response. Two main classes of NKT cells (Type I and II) exist that express different antigen receptors (TCRs) and respond to different glycolipids presented by the shared antigen-presenting molecule CD1d. Type I NKT cells respond rapidly to the prototypical antigen -galactosylceramide (-GalCer) and can secrete both pro- and anti-inflammatory cytokines, while Type II NKT cells recognize the self-glycolipid sulfatide and are thought to be controlling autoimmunity. The cytokine profile of Type I NKT cells can be altered using modified synthetic glycolipids to produce the cytokine response of choice. Through biophysical TCR binding affinity measurements, as well as crystallographic studies of how the TCR engages different CD1dpresented glycolipids, we and others have identified the structural basis of glycolipid recognition by NKT cells. The TCR of Type I NKT cells binds to CD1d with a conserved footprint, while inducing structural changes in both CD1d and the glycolipid antigens. This conserved TCR binding mode allows for the design of glycolipid antigens, predominantly analogs of -GalCer in an attempt to obtain glycolipids that elicit a particular cytokine profile
