Sideways lipid presentation by the antigen-presenting molecule CD1c

Cao, Thinh-Phat, Liao, Guan-Ru, Cheng, Tan-Yun, Chen, Yanqiong, Ciacchi, Laura, Fulford, Thomas S., Farquhar, Rachel, Kollmorgen, Jade, Mayfield, Jacob A., Uldrich, Adam P., Ng, Emily Zhi Qing, Ogg, Graham S., Godfrey, Dale I., Gherardin, Nicholas A., Chen, Yi-Ling, Moody, D. Branch, Shahine, Adam and Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 2025. Sideways lipid presentation by the antigen-presenting molecule CD1c. Nature Communications 10.1038/s41467-025-67732-2

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Abstract

For the MHC, MR1 and CD1 systems, antigen recognition involves contact of the membrane distal surfaces of both the αβ T cell receptor (TCR) and the antigen-presenting molecule. Whether other antigen display mechanisms by antigen-presenting molecules operate remains unknown. Here, we report mass spectrometry analyses of endogenous lipids captured by CD1c when bound to an autoreactive αβ TCR. CD1c binds twenty-six lipid species with bulky headgroups that cannot 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 are oriented sideways so that their polar headgroups protrude laterally through a side portal of the CD1c molecule - an evolutionarily conserved structural feature. The sideways-presented ganglioside headgroups do not hinder TCR binding and so represent a mechanism that allows autoreactive TCR recognition of CD1c. In addition, ex vivo studies showed that the sideways-presented gangliosides can also represent TCR recognition determinants. These findings reveal that CD1c simultaneously presents two lipid antigens from the top and side of its cleft, a general mechanism that differs markedly from other antigen-presenting molecules.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Publisher:	Nature Research
Date of Acceptance:	5 December 2025
Last Modified:	07 Jan 2026 14:15
URI:	https://orca.cardiff.ac.uk/id/eprint/183677

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