Sideways lipid presentation by the antigen-presenting molecule CD1c

Rossjohn, J.; Shahine, A.; Cao, T.-P.; Moody, B.

doi:10.1101/2025.10.27.684910

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bioRxiv · 10.1101/2025.10.27.684910

Sideways lipid presentation by the antigen-presenting molecule CD1c

Rossjohn, J.·Shahine, A.·Cao, T.-P.·Moody, B.

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Abstract

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.

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Rossjohn, J., Shahine, A., Cao, T.-P., Moody, B.. 2025-10-28. Sideways lipid presentation by the antigen-presenting molecule CD1c. https://doi.org/10.1101/2025.10.27.684910

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