The Evolving Portrait of γδ TCR Recognition Determinants

Abstract

In αβ T cells, immunosurveillance is enabled by the αβ TCR, which corecognizes peptide, lipid, or small-molecule Ags presented by MHC- and MHC class I-like Ag-presenting molecules, respectively. Although αβ TCRs vary in their Ag recognition modes, in general they corecognize the presented Ag and the Ag-presenting molecule and do so in an invariable "end-to-end" manner. Quite distinctly, γδ T cells, by way of their γδ TCR, can recognize ligands that extend beyond the confines of MHC- and MHC class I-like restrictions. From structural studies, it is now becoming apparent that γδ TCR recognition modes can break the corecognition paradigm and deviate markedly from the end-to-end docking mechanisms of αβ TCR counterparts. This brief review highlights the emerging portrait of how γδ TCRs can recognize diverse epitopes of their Ags in a manner reminiscent to how Abs recognize Ags.

Figure 1.. Docking topology of γδ TCRs upon MHC-like molecules.

A. Expanded alignment of γδ TCR complex structures upon an MHC I-like molecule. All molecules are represented as a surface with the γ-chain of each TCR in a lighter shade and the δ-chain in a darker shade of the orange (G7 TCR), purple (G8 TCR), green (G83.C4 TCR), yellow (DP10 TCR), red (9C2 TCR), blue (5F3 TCR), and pink (CO3 TCR). Dots and projections symbolise the approximate centre of the interface. B-H) Contribution of Vγ and Vδ towards BSA at the interface of the TCR and MHC-like molecule. Complexes are initially displayed in cartoon form within a silhouette of the surface of the complex. The BSA of the MHC-like molecule corresponding to each chain of the γδ TCR is highlighted in their respective colours with the Vγ chain being depicted in the lighter shade. B. Murine G8 TCR in complex with T22. PDB: 1YPZ. C. 5F3 TCR in complex with HLA-A*02 presenting MART-1 peptide. PDB: 6D7G. D. DP10 TCR in complex with CD1d presenting sulfatide. PDB: 4MNG. E. 9C2 TCR in complex with CD1d presenting αGalCer. PDB: 4LHU. F. CO3 TCR in complex with CD1a presenting sulfatide. PDB: 7RYN. G. G7 TCR in complex with MR1 presenting 5-OP-RU. PDB: 6MWR. H. G83.C4 in complex with MR1 presenting 5-OP-RU. PDB: 7LLI. Molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, USA.

Figure 2:. Key tryptophan residues in the germline and non-germline encoded regions of γδ TCR paratopes.

Cartoon representation of the interfacial tryptophan residues from the TCR δ-chain, with germline and non-germline residues coloured brown and dark green, respectively for the following: A. G8 TCR in complex with murine T22. PDB: 1YPZ. B. 5F3 TCR in complex with HLA-A*02 presenting MART-1 peptide. PDB: 6D7G. C. DP10 TCR in complex with CD1d presenting sulfatide. PDB: 4MNG. D. 9C2 TCR in complex with CD1d presenting αGalCer. PDB: 4LHU. E. CO3 TCR in complex with CD1a presenting sulfatide. PDB: 7RYN. F. G7 TCR in complex with MR1 presenting 5-OP-RU. PDB: 6MWR. G. G83.C4 in complex with MR1 presenting 5-OP-RU. PDB: 7LLI. Contact residues on the MHC I-like molecule are also displayed. Molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, USA.