Structure of a fully assembled γδ T cell antigen receptor

Area of Science:

• Immunology
• Structural Biology
• Molecular Biology

Background:

• T cells, crucial for adaptive immunity, exist as αβ and γδ lineages, distinguished by their T-cell receptors (TCRs).
• While the structure of αβ T-cell receptors is well-characterized, the architecture of γδ T-cell receptors remains unknown.
• γδ T-cell receptors are known to recognize a broader range of ligands than αβ T-cell receptors, suggesting unique structural properties.

Purpose of the Study:

• To determine the three-dimensional structure of a human γδ T-cell receptor complex.
• To compare the structural organization and flexibility of γδ TCRs with known αβ TCR structures.
• To understand how γδ TCR structure relates to its diverse ligand-binding capabilities and signaling functions.

Main Methods:

• Cryogenic electron microscopy (cryo-EM) was employed to visualize the assembled human Vγ8Vδ3 TCR-CD3 complex.
• The complex was studied in association with MR1 and anti-CD3ε antibody fragments.
• Structural analysis focused on the arrangement and interactions of TCR variable domains and conserved CD3 subunits.

Main Results:

• The study determined the structure of a human γδ TCR-CD3 complex, revealing conserved CD3 subunit arrangement similar to αβ TCRs.
• Unlike the rigid αβ TCR, the γδ TCR exhibited significant conformational heterogeneity due to its transmembrane helix tethering.
• Modifying the γδ TCR to resemble αβ TCR structure enhanced signaling, indicating a trade-off between ligand diversity and signaling efficiency.

Conclusions:

• The γδ TCR structure demonstrates remarkable plasticity, adapting its flexibility to accommodate diverse ligand recognition.
• This structural adaptability is a key evolutionary feature enabling γδ T cells to fulfill distinct immunological roles.
• The findings redefine the TCR as a versatile receptor capable of signaling through both rigid and flexible conformations.