CD1d-restricted Type I Natural Killer T (iNKT) cells are an evolutionary conserved T cell population characterized by features of both the innate and adaptive immune response. INKT cells respond rapidly to the prototypical antigen a-galactosylceramide (a-GalCer) and can secrete both inflammatory (TH1, IFN-g) and anti-inflammatory (TH2, IL-4) cytokines. The cytokine profile can be biased toward either TH1 or TH2 by changing the structure of the glycolipid antigen. Through both biophysical TCR binding affinity measurements, as well as crystallographic studies of how the TCR engages different CD1d-presented glycolipids, we and others have identified the structural basis of glycolipid recognition by iNKT cells. The TCR of iNKT cells binds to CD1d with a conserved footprint, while inducing structural changes in both CD1d and the glycolipid antigen. This conserved TCR binding mode allows for the design of glycolipid antigens, predominantly analogs of a-GalCer in an attempt to obtain glycolipids that elicit a particular cytokine profile. We are especially interested in identifying novel TH1 skewing antigens, since they have great potential as vaccine adjuvants. I will present our ongoing work on characterizing novel CD1d-restricted antigens, which led us to a surprising discovery.