Sideways lipid presentation by the antigen-presenting molecule CD1c

Journal article

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.

Authors: Cao, T; Liao, G; Cheng, T; Chen, Y; Ciacchi, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 17
• Issue: 1
• Article number: 998
• Publication date: 2025-12-31
• Acceptance date: 2025-12-05
• DOI: 10.1038/s41467-025-67732-2
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: T-cell receptor; Antigen presentation; Jurkat cells; Mechanism (biology); Ganglioside; Plasma protein binding; CD1; T cell; Molecule; Antigen