Journal
PROTEIN ENGINEERING DESIGN & SELECTION
Volume 35, Issue -, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/protein/gzab034
Keywords
T cell receptor (TCR); high-throughput TCR alpha:beta sequencing; library immortalization; affinity-based screening
Funding
- Richard M. Schulze Family Foundation
- Randy Shaver Cancer Research and Community Fund
- Matt Cwiertny Foundation
- University of Minnesota Foundation
- Wellcome Trust [100326/Z/12/Z]
- University of Kansas Cancer Center
- US Department of Defense [W81XWH1810296]
- US National Institutes of Health [DP5OD023118, P20GM103638, P20GM103418, R21CA230487]
- U.S. Department of Defense (DOD) [W81XWH1810296] Funding Source: U.S. Department of Defense (DOD)
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This study developed a new high-throughput approach for functional evaluation of TCRs. By leveraging physically linked TCR libraries, it enabled repertoire-scale analysis of TCR binding to multiple pMHCs. Affinity-based functional mapping in conjunction with next-generation sequencing was used to track antigen-specific TCRs.
Functional analyses of the T cell receptor (TCR) landscape can reveal critical information about protection from disease and molecular responses to vaccines. However, it has proven difficult to combine advanced next-generation sequencing technologies with methods to decode the peptide-major histocompatibility complex (pMHC) specificity of individual TCRs. We developed a new high-throughput approach to enable repertoire-scale functional evaluations of natively paired TCRs. In particular, we leveraged the immortalized nature of physically linked TCR alpha:beta amplicon libraries to analyze binding against multiple recombinant pMHCs on a repertoire scale, and to exemplify the utility of this approach, we also performed affinity-based functional mapping in conjunction with quantitative next-generation sequencing to track antigen-specific TCRs. These data successfully validated a new immortalization and screening platform to facilitate detailed molecular analyses of disease-relevant antigen interactions with human TCRs.
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