Summary: Mouse CDl (mCDl) is an antigen-presenting molecule that is constitutively expressed by most bone marrow-derived cells. Peptides with a hydrophobic binding motif can bind to mCDl, and the peptide-CDl complex is recognized by CD8+ cytolytic T cells. In contrast, NK1.1+ T cells, which are CD8-, are autoreactive for mCD 1 molecules. This autore-activity, along with the ability of NK T cells to rapidly produce large amounts of cytokine, has led to the suggestion that these cells may be immunoregulatory We have shown that die mCD l -autoreactive T cells can distinguish between different cell types that express similar levels of mCDl, suggesting that mCDl -bound autologous ligands may be critical for T-cell stimulation. Consistent with this, some of these mCDl-restricted T cells can recognize the glycolipid a-galactosyiceramide presented by mCDl, while others do not respond. The mCDl crystal structure reveals a deep and narrow hydrophobic antigen-binding site which can more easily bind lipid antigens than the long hydrophobic peptides that we have defined as mCDl antigens. The ability of mCDl to bind and present two different types of ligands raises the question as to how mCDl can accommodate both types of antigens.