An Engineered T Cell Receptor Variant Realizes the Limits of Functional Binding Modes

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• T cell receptors (TCRs) are crucial for cellular immunity, recognizing peptide-MHC complexes.
• Natural TCRs bind to the peptide-MHC surface, requiring structural and chemical compatibility.

Purpose of the Study:

• To describe a molecularly evolved TCR variant with altered binding properties.
• To investigate the impact of modified TCR binding geometry on T cell signaling.

Main Methods:

• Molecular evolution of a TCR variant.
• Analysis of TCR binding to HLA-A2.
• Assessment of T cell signaling in solution and at cell-cell interfaces.

Main Results:

• An engineered TCR variant binds HLA-A2 independently of the presented peptide.
• The variant exhibits a perturbed binding geometry, positioning the TCR away from the peptide-binding groove.
• This unique geometry results in a lack of T cell signaling, attributed to steric hindrance at the cell interface.

Conclusions:

• Receptor binding geometry significantly influences T cell function.
• Germline-encoded TCR residues are critical for productive T cell recognition and signaling.