γδ T cell receptor recognition of CD1d in a lipid-independent manner

Rice, Michael T., Gunasinghe, Sachith D., Sok, Chhon Ling, Pan, Mengqi, Lay, Chan-Sien, Gully, Benjamin S. and Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 2025. γδ T cell receptor recognition of CD1d in a lipid-independent manner. Nature Communications 10.1038/s41467-025-67653-0

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Abstract

The monomorphic antigen-presenting molecule CD1d presents lipid antigens to both αβ and γδ T cells. While type I natural killer T cells (NKT) display exquisite specificity for CD1d presenting α-galactosylceramide (α-GalCer), the extent of lipid specificity exhibited by CD1d-restricted γδ T cells remains unclear. Here, we demonstrate that human γδ T cell receptors (TCRs) can recognise CD1d in either a lipid-dependent or lipid-independent manner with weak to moderate affinity. Using small-angle X-Ray scattering, we find that γδ TCR-CD1d binding modality is conserved across distinct CD1d-restricted TCRs. In functional assays, CD1d γδ TCR affinity was a poor predictor of γδ T cell line activation. Moreover, CD1d presenting endogenous lipids was sufficient to stimulate T cell activation and induce γδ TCR-CD3 clustering and phosphorylation in a dose-dependent manner. Elongation of the γδ TCR-CD3 complex by the inclusion of the Cγ2 and Cγ3 -encoded constant domains perturbed cellular activation whilst maintaining the ability to form functional γδ TCR clusters. The crystal structure of a Vδ1 γδ+ TCR-CD1d complex showed that the γδ TCR sat atop of the CD1d antigen-binding cleft but made no contacts with the presented lipid antigen. These findings provide a molecular basis for lipid-independent CD1d recognition by γδ TCRs.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Publisher:	Nature Research
Date of First Compliant Deposit:	6 January 2026
Date of Acceptance:	5 December 2025
Last Modified:	06 Jan 2026 16:15
URI:	https://orca.cardiff.ac.uk/id/eprint/183611

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