Targeting virus entry and membrane fusion through specific peptide/MHC complexes using a high-affinity T-cell...

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• T-cell receptors (TCRs) mediate T-cell recognition of peptide-major histocompatibility complex (pMHC) ligands.
• TCR engagement, with co-stimulation, triggers T-cell effector functions.

Purpose of the Study:

• To engineer measles viruses to display single-chain TCRs (scTCRs) for targeted cell entry.
• To investigate the ability of scTCR-engineered measles viruses to bind and mediate entry via specific pMHC complexes.
• To establish a quantitative method for assessing pMHC complex expression on target cells.

Main Methods:

• Grafting a high-affinity 2C scTCR onto the measles virus hemagglutinin (H) protein.
• Assessing virus entry and cell-to-cell fusion mediated by the scTCR-H protein.
• Quantifying the dependence of virus entry efficiency on target cell pMHC complex density.

Main Results:

• Engineered measles viruses successfully recognized and bound to specific pMHC ligands (SIYRYYGL/mouse K(b)).
• scTCR display conferred new specificity to measles virus entry and cell fusion.
• Virus entry efficiency correlated positively with target cell pMHC complex expression levels, showing a threshold effect above 2500 complexes/cell.

Conclusions:

• Measles virus attachment proteins can be engineered to display scTCRs, enabling targeted virus entry and fusion.
• This approach extends targeting capabilities to specific pMHC ligands, offering a new strategy for viral vector design.
• The study provides a novel quantitative readout for measuring cell surface pMHC complex expression.