Variant MHC Peptide Ligands for T Cell Activation
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Solution Overview
Problem
Current methods struggle to effectively activate self-reactive T cells in a peptide-specific manner to target autoimmune responses against cancers and persistent virus infections.
Innovation Solution
The use of variant MHC molecules with specific amino acid changes that interact with T cell receptors, combined with peptide epitopes, to activate T cells and focus immune responses against specific pathological conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type MHC molecules are used to present self-peptides, then T cell activation threshold is maintained for self-tolerance, but self-reactive T cells cannot be activated to target pathological conditions
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues in the MHC molecule at the TCR interaction interface (such as positions 72, 76, 79 in the alpha helix). These parameter changes alter the binding affinity and activation threshold of the MHC-peptide complex, enabling it to activate self-reactive T cells that would normally be tolerized, while still maintaining peptide-specificity for targeting pathological conditions like cancer and viral infections.
2Adaptability or versatility
If MHC molecules are modified to activate self-reactive T cells, then ability to target autoimmune responses is improved, but specificity of T cell response may be reduced
Solution Approach 1:
The patent applies local quality by making specific, localized amino acid substitutions only at the TCR interaction interface of the MHC molecule (such as positions 72, 76, 79), while leaving the peptide-binding groove and other regions unchanged. This localized modification approach preserves the peptide-specificity of the T cell response while enabling activation of self-reactive T cells through altered TCR binding properties.
Data Source
AI summary
Materials and methods for identifying and using MHC molecule variants for activating self-reactive T cells in a peptide-specific manner, and their use to focus autoimmune cellular responses against diseases such as cancers and persisting viral infections, are described.