Universal open MHC-I molecules for rapid peptide loading and enhanced complex stability across HLA allotypes

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Major histocompatibility complex class I (MHC-I) molecules are crucial for immune response but are inherently unstable with suboptimal ligands.
• This instability poses challenges in identifying disease-relevant antigens and developing antigen-specific T cell receptor (TCR)-based therapeutics.

Purpose of the Study:

• To engineer conformationally stable, peptide-receptive MHC-I molecules.
• To overcome the limitations of polymorphic and unstable MHC-I structures for therapeutic development.

Main Methods:

• Engineered disulfide bond between heavy chain (HC) and β2 microglobulin (β2m) to create "open MHC-I".
• Biophysical characterization (e.g., thermal stability assays).
• Solution Nuclear Magnetic Resonance (NMR) spectroscopy to analyze structural and dynamic effects.

Main Results:

• Open MHC-I molecules exhibit enhanced thermal stability with low- to moderate-affinity peptides.
• Disulfide bond induces conformational changes, stabilizing MHC-I in an open state.
• Facilitates peptide exchange across diverse human leukocyte antigen (HLA) allotypes and MHC-Ib molecules.

Conclusions:

• Engineered open MHC-I provides a universal, stable platform for antigen discovery and TCR repertoire analysis.
• This platform supports the development of autologous therapeutics targeting polymorphic HLA-I and MHC-Ib molecules.