Structural and functional consequences of altering a peptide MHC anchor residue

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• T cell receptors (TCRs) discriminate between various peptide-MHC ligands to initiate immune responses.
• Understanding the structural basis of TCR ligand discrimination is crucial for deciphering immune recognition mechanisms.

Purpose of the Study:

• To investigate how a single amino acid substitution in a peptide affects TCR recognition and subsequent T cell activation.
• To elucidate the structural consequences of peptide modifications on the peptide-MHC complex and its interaction with TCRs.

Main Methods:

• X-ray crystallography was used to determine the structures of two peptide/MHC class II complexes differing by a single amino acid substitution (E73D) at the P6 anchor position.
• Detailed structural comparisons of independently determined crystal structures at 1.9 Å resolution were performed.
• T cell responses and TCR binding affinities were analyzed to assess functional consequences.

Main Results:

• A single amino acid substitution, altering a buried methylene group, significantly modified the TCR recognition surface of the peptide-MHC complex.
• Conformational changes were observed in the peptide backbone (P5-P8) and at a distal residue (LeuP8), while the MHC class II molecule conformation remained unchanged.
• The substitution reduced the potency of the ligand for a specific T cell (3.L2) by 1000-fold, despite similar binding affinities but altered kinetics of soluble TCR binding.

Conclusions:

• Subtle variations in peptide presentation by MHC molecules can profoundly influence T cell activation and signaling pathways.
• The study highlights the exquisite sensitivity of T cell discrimination to minute changes in antigen structure.
• These findings have implications for understanding immune responses in health and disease, and for designing immunotherapies.