Function-preserving CD8⁺ T Cell Immunogenicity minimization through protein design

Protein design can tune CD8⁺ T cell immunogenicity while preserving function, with epitope-eliminated de novo luciferase variants eliciting little detectable response across 5 mouse alleles.

• Why it matters: Foreign proteins in adoptive cell therapy can trigger cytotoxic CD8⁺ T cell responses, creating a need to reduce immunogenicity without sacrificing protein function.
• What they did: A computational framework combined structure-guided sequence design with MHC class I epitope prediction, optimizing a de novo luciferase across 5 mouse alleles and 25 human MHC-I alleles.
• The result: In mice immunized with mRNA-lipid nanoparticles, variants with few MHC-I epitopes elicited little detectable CD8 T cell response, while variants with multiple epitopes induced robust responses.