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Scalable TCR synthesis and screening enable antigen reactivity mapping in vitiligo
Stephanie A Gaglione1, Rachit S Mukkamala2, Chirag Krishna3
1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA, USA.
Immunity
|January 29, 2026
Summary
Researchers developed TCR rapid assembly for functional testing (TCRAFT) to rapidly screen thousands of T cell receptors (TCRs) against antigens. This method aids in understanding immune responses in diseases like vitiligo and cancer, advancing immunotherapy development.
Area of Science:
- Immunology
- Molecular Biology
- Bioinformatics
Background:
- T cell receptors (TCRs) are crucial for adaptive immunity, recognizing specific antigens to initiate targeted responses.
- Mapping the vast diversity of TCRs to their cognate antigens at a large scale is a significant challenge in immunology.
- Understanding TCR-antigen interactions is vital for diagnosing and treating immune-related diseases and developing effective immunotherapies.
Purpose of the Study:
- To develop a scalable and cost-effective method for synthesizing and functionally screening large libraries of TCRs.
- To map TCRs from patients with autoimmune diseases (vitiligo) and cancer (pancreatic ductal adenocarcinoma) to specific antigens.
- To investigate shared features of disease-relevant T cells in autoimmunity and cancer.
Main Methods:
- Developed TCR rapid assembly for functional testing (TCRAFT), a modular strategy for rapid, inexpensive construction of large TCR pools with maintained TCRα/β pairing.
- Applied TCRAFT to reconstruct over 3,800 TCRs from vitiligo patient samples.
- Utilized RAPTR (Recognition Activation based Protein-Transducer of RNA) for library-on-library screening to map TCRs to peptide-major histocompatibility complexes (pMHCs).
- Synthesized and screened over 30,800 TCRs from pancreatic ductal adenocarcinoma donors to demonstrate scalability.
Main Results:
- Successfully reconstructed and mapped thousands of TCRs from vitiligo patients to specific antigens.
- Identified shared transcriptomic signatures and clonal expansion patterns between vitiligo-associated T cells and those found in melanoma, suggesting commonalities in disease-relevant T cells.
- Demonstrated the scalability of the TCRAFT approach by screening over 30,800 TCRs from pancreatic cancer patients.
Conclusions:
- TCRAFT significantly expands the scale and accessibility of TCR-antigen screening.
- The findings highlight potential shared immunological mechanisms in autoimmune diseases and cancer.
- This approach is critical for advancing our understanding of immunity and developing novel immunotherapies.
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