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

## TL;DR

This paper shows how γδ T cells can recognize CD1d molecules without needing a specific lipid, revealing a new way these immune cells detect antigens.

## Contribution

The study reveals the molecular mechanism of lipid-independent CD1d recognition by γδ T cell receptors.

## Key findings

- γδ T cell receptors can recognize CD1d in a lipid-independent manner.
- The structure of a γδ TCR-CD1d complex shows no contact with the presented lipid.
- Endogenous lipids on CD1d are sufficient to activate γδ T cells.

## 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.

T cells can recognise lipid antigen in the context of CD1d molecules. Here, the authors show that γδ T cell activation in response to CD1d differs from that of αβ T cells and determine the structure of a γδ T cell receptor that binds to CD1d independently of the presented lipid.