Sideways lipid presentation by the antigen-presenting molecule CD1c

Here we report mass spectrometry analyses of endogenous lipids captured by CD1c when bound to an autoreactive {beta}TCR. CD1c bound twenty-six lipids with bulky headgroups that could not fit within the tight TCR-CD1c interface. We determined the crystal structures of CD1c presenting several gangliosides, revealing a general mechanism whereby two lipids, rather than one, are bound in the CD1c cleft. Bulky lipids were orientated sideways so that their polar headgroups protruded laterally through a side portal of the CD1c molecule - an evolutionarily conserved structural feature. The sideways presented ganglioside headgroups did not hinder TCR binding and so represent a mechanism that allows autoreactive TCR recognition of CD1c. In addition, ex vivo studies showed sideways presented gangliosides could also represent TCR recognition determinants. These findings reveal a general mechanism whereby CD1c simultaneously presents two lipid antigens from the top and side of its cleft that differs markedly from other antigen-presenting molecules.