Mouse CD1d1, a member of the CD1 family of evolutionarily conserved ma
jor histocompatibility antigen-like molecules, controls the differenti
ation and function of a T lymphocyte subset, NK1(+) natural T cells, p
roposed to regulate immune responses. The CD1d1 crystal structure reve
aled a large hydrophobic binding site occupied by a ligand of unknown
chemical nature. Mass spectrometry and metabolic radiolabeling were us
ed to identify cellular glycosylphosphatidylinositol as a major natura
l ligand of CD1d1. CD1d1 bound glycosylphosphatidylinositol through it
s phosphatidylinositol aspect with high affinity. Glycosylphosphatidyl
inositol or another glycolipid could be a candidate natural ligand for
CD1d1-restricted T cells.