Structural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM
Kei Saotome1, Drew Dudgeon2, Kiersten Colotti2
1Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA. kei.saotome@regeneron.com.
Abstract:
The recognition of antigenic peptide-MHC (pMHC) molecules by T-cell receptors (TCR) initiates the T-cell mediated immune response. Structural characterization is key for understanding the specificity of TCR-pMHC interactions and informing the development of therapeutics. Despite the rapid rise of single particle cryoelectron microscopy (cryoEM), x-ray crystallography has remained the preferred method for structure determination of TCR-pMHC complexes. Here, we report cryoEM structures of two distinct full-length α/β TCR-CD3 complexes bound to their pMHC ligand, the cancer-testis antigen HLA-A2/MAGEA4 (230-239). We also determined cryoEM structures of pMHCs containing MAGEA4 (230-239) peptide and the closely related MAGEA8 (232-241) peptide in the absence of TCR, which provided a structural explanation for the MAGEA4 preference displayed by the TCRs. These findings provide insights into the TCR recognition of a clinically relevant cancer antigen and demonstrate the utility of cryoEM for high-resolution structural analysis of TCR-pMHC interactions.
Insights
T-cell receptors (TCR) recognize cancer antigens presented by peptide-MHC (pMHC) molecules. We used cryo-electron microscopy (cryoEM) to determine the structures of TCR-pMHC complexes, revealing molecular details of this critical immune interaction.
Area of Science:
- Immunology
- Structural Biology
- Biochemistry
Background:
- T-cell receptors (TCR) binding to peptide-MHC (pMHC) complexes is central to adaptive immunity.
- Understanding TCR-pMHC specificity is crucial for developing targeted immunotherapies.
- X-ray crystallography has been dominant, but cryo-electron microscopy (cryoEM) offers complementary structural insights.
Purpose of the Study:
- To determine high-resolution cryoEM structures of TCR-CD3 complexes bound to the cancer-testis antigen HLA-A2 presenting MAGEA4 peptide.
- To elucidate the structural basis for TCRs' specific recognition of MAGEA4 over closely related peptides.
- To demonstrate the utility of cryoEM for analyzing TCR-pMHC interactions.
Main Methods:
- Single particle cryo-electron microscopy (cryoEM) was employed to resolve complex structures.
- Structures of TCR-CD3 complexes bound to HLA-A2/MAGEA4 (230-239) were determined.
- CryoEM structures of HLA-A2 presenting MAGEA4 (230-239) and MAGEA8 (232-241) peptides alone were also solved.
Main Results:
- High-resolution cryoEM structures of two distinct TCR-CD3 complexes bound to HLA-A2/MAGEA4 were obtained.
- Structures of pMHC complexes revealed molecular details explaining TCR preference for MAGEA4.
- The structural data provided insights into the specific recognition mechanism.
Conclusions:
- CryoEM is a powerful tool for high-resolution structural determination of TCR-pMHC complexes.
- The study provides structural explanations for TCR recognition of a relevant cancer antigen.
- Findings advance understanding of T-cell recognition and inform therapeutic strategies.
