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A Synthetic Cytotoxic T cell Platform for Rapidly Prototyping TCR Function
Govinda Sharma1, James Round1, Fei Teng1
1Michael Smith Genome Sciences Centre; British Columbia Cancer Research Institute; 675 W 10 Ave, Vancouver, BC, V5Z 1L3; Canada.
Biorxiv : the Preprint Server for Biology
|December 4, 2023
Summary
Researchers developed a new platform to test T cell receptor (TCR) function, enabling precise measurement of cytotoxic potential and cross-reactivity. This tool facilitates the optimization of therapeutic TCRs for enhanced efficacy and reduced off-target effects.
Area of Science:
- Immunology
- Cell Biology
- Biotechnology
Background:
- Profiling T cell receptors (TCRs) for cytotoxic potency and cross-reactivity is challenging due to limitations in model systems.
- Existing methods struggle to test TCRs across diverse HLA alleles and antigen arrays.
Approach:
- Developed a novel universal prototyping platform using engineered YT-Indy and K562 cell lines.
- Implemented a granzyme-activatable sensor for T cell cytotoxicity.
- Enabled facile recombinant expression of TCR, peptide, and MHC sequences.
Key Points:
- Successfully reconstituted surface TCR complex in YT-Indy cells at biologically relevant levels.
- Demonstrated sensitive detection of antigen-specific responses in multiple model TCRs.
- Preserved target cells for 24 hours in co-culture, allowing for downstream characterization.
Conclusions:
- The bioplatform allows rapid expression and characterization of TCR responses.
- Facilitates new knowledge generation on TCR recognition patterns.
- Enables optimization of therapeutic TCRs for improved cytotoxic potential and reduced cross-reactivity.
