Lipid antigens have to be long enough for cytotoxic granules (green) to move from the rear of NKT cells to the immunological synapse (left to right).

Lipid antigens are presented to NKT cells by the surface glycoprotein CD1d. These fatty antigens are composed of a hydrophilic head that is exposed to the TCR on the NKT cells, and two hydrophobic tails. Each tail—an acyl chain and a fatty acid chain—is tucked away inside separate grooves within the CD1d molecule.

Previous studies showed that shorter lipid chains destabilize the binding of the lipid antigen to CD1d. Whereas some of these short ligands simply reduce the ability of CD1d to activate an NKT cell, others switch the NKT response from interferon to interleukin-4 production.

McCarthy et al. now find that shortening either the acyl or the fatty acid chain destabilizes the CD1d-lipid complex. The shorter fatty acid chain, however, also reduces the binding affinity between the CD1d-lipid complex and the TCR. The NKT cells are therefore unable to induce clustering of CD1d-lipid complexes and fail to form a productive synapse with the antigen presenting cell. The authors propose that the stumpy fatty acid chain doesn't completely fill its CD1d groove, which consequently collapses. This new conformation might lead to a less stable interaction between the complex and the TCR.