Table 1.

Lipids play differing positive and negative regulatory roles in the older corecognition model and the newly proposed direct recognition model, respectively.

	Corecognition Model	Direct Recognition Model
TCR Target	CD1 and lipid	CD1
TCR Epitope	periportal CD1 residues and hydrophilic cap of lipid	A’ roof and periportal residues of CD1
Activating Ligands	amphipathic lipids protrude for TCR contact	small lipids reside inside CD1
Abundance of Ligand	low	high
Mechanism of Activation	epitope discrimination	absence of TCR interference
Non-activating Lipids	amphiphathic lipid protrudes but fails to bind the TCR	dominant negative blockade of TCR binding to the A’ roof
Default Outcome of CD1-TCR Contact	non-activation (unless rare antigen present)	activation (unless blocker is dominant)
Ligand-based Therapy	activation-based adjuvancy or immunization	inhibition of autoimmune response