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Gene Signatures of T-Cell Activation Can Serve as Predictors of Functionality for SARS-CoV-2-Specific T-Cell Receptors

The importance of T cells in controlling SARS-CoV-2 infections has been demonstrated widely, but insights into the quality of these responses are still limited due to technical challenges. Indeed, understanding the functionality of the T-cell receptor (TCR) repertoire of a polyclonal antigen-specifi...

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Detalles Bibliográficos
Autores principales: Mateyka, Laura M., Strobl, Philipp M., Jarosch, Sebastian, Scheu, Sebastian J. C., Busch, Dirk H., D’Ippolito, Elvira
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9611811/
https://www.ncbi.nlm.nih.gov/pubmed/36298482
http://dx.doi.org/10.3390/vaccines10101617
Descripción
Sumario:The importance of T cells in controlling SARS-CoV-2 infections has been demonstrated widely, but insights into the quality of these responses are still limited due to technical challenges. Indeed, understanding the functionality of the T-cell receptor (TCR) repertoire of a polyclonal antigen-specific population still requires the tedious work of T-cell cloning or TCR re-expression and subsequent characterization. In this work, we show that it is possible to discriminate highly functional and bystander TCRs based on gene signatures of T-cell activation induced by recent peptide stimulation. SARS-CoV-2-specific TCRs previously identified by cytokine release after peptide restimulation and subsequent single-cell RNA sequencing were re-expressed via CRISPR-Cas9-mediated gene editing into a Jurkat-based reporter cell line system suitable for high-throughput screening. We could observe differences in SARS-CoV-2 epitope recognition as well as a wide range of functional avidities. By correlating these in vitro TCR engineered functional data with the transcriptomic profiles of the corresponding TCR-expressing parental T cells, we could validate that gene signatures of recent T-cell activation accurately identify and predict truly SARS-CoV-2-specific TCRs. In summary, this work paves the way for alternative approaches useful for the functional analysis of global antigen-specific TCR repertoires with largely improved throughput.