Structure of a human gammadelta T-cell antigen receptor

Area of Science:

• Immunology
• Structural Biology
• Molecular Biology

Background:

• Gamma delta T-cell receptors (gammadelta TCRs) recognize intact proteins or non-peptide compounds, unlike alphabeta TCRs.
• Approximately 5% of peripheral blood T cells express gammadelta TCRs, primarily recognizing non-peptide phosphorylated antigens.
• Understanding gammadelta TCR structure is crucial for elucidating their unique antigen recognition mechanisms.

Purpose of the Study:

• To determine the high-resolution structure of a human phosphoantigen-reactive gammadelta TCR.
• To compare the structural features of gammadelta TCRs with alphabeta TCRs and antibodies.
• To provide a structural basis for the recognition of phosphoantigens by specific gammadelta TCR gene segments.

Main Methods:

• X-ray crystallography was used to determine the structure of a human gammadelta TCR at 3.1 Å resolution.
• Comparative structural analysis was performed between gammadelta TCRs, alphabeta TCRs, and antibodies.
• Analysis of complementarity-determining regions (CDRs) and domain orientations was conducted.

Main Results:

• A unique orientation of variable (V) and constant (C) regions was observed in the gammadelta TCR, stemming from a small angle between Vgamma and Cgamma domains.
• The V domain's CDRs present a chemically plausible binding site for phosphorylated antigens, explaining the use of Vgamma9 and Vdelta2 gene segments.
• Significant structural differences were noted in the C domains (Cgamma and Cdelta) and their inter-chain disulfide bond compared to alphabeta TCRs.

Conclusions:

• The determined structure provides a molecular explanation for phosphoantigen recognition by gammadelta TCRs.
• Distinct structural features in gammadelta TCR C domains suggest they may form different recognition/signaling complexes than alphabeta TCRs.
• This structural insight advances our understanding of T-cell receptor diversity and immune recognition pathways.