The molecular basis of CD1-mediated presentation of lipid antigens

The CD1 family of proteins mediates a newly described pathway for presentat ion of lipids and glycolipids for specific recognition by T cells. All four of the known human CD1 proteins (CD1a, CD1b, CD1c and CD1d) as well as mur ine CD1d have now been shown to mediate T-cell recognition of lipid or glyc olipid antigens. These antigens include naturally occurring foreign glycoli pids from intracellular pathogens or synthetic glycolipids that are related in structure to mammalian glycolipids. The CD1b and CD1d-presented antigen s differ in their fine structures but reveal a general motif in which a rig id hydrophilic cap is bound to two aliphatic hydrocarbon chains. Different T-cell populations recognize individual antigens without cross-reactivity t o closely related antigen structures or CD1 isoforms, documenting the compl exity and fine specificity of CD1-mediated T-cell responses. Mapping of the molecular determinants of recognition for CD1b and CD1d-presented antigens reveals that T cells discriminate the fine structure of the hydrophilic ca p of the antigen, but both the length and structure of the lipid chains may be altered without loss of recognition. This pattern of lipid antigen reco gnition may be accounted for by a simple molecular mechanism of presentatio n that parallels the known mechanism for presentation of peptides, but solv es the special problems related to the hydrophobic chemical nature of the l ipid antigens. We propose that CD1 binds antigen by accommodating the two l ipid tails within the hydrophobic groove of its two membrane distal domains , positioning the rigid hydrophilic cap of the antigen on the solvent-expos ed surface of the CD1 protein, where it can directly contact the T-cell ant igen receptor. This model provides a molecular basis for recognition of a n ew and diverse set of T-cell antigens contained within the lipid bilayers o f cellular membranes.