Resolving SARS-CoV-2 CD4⁺ T cell specificity via reverse epitope discovery.

Area of Science:

• Immunology
• Virology
• Computational Biology

Background:

• Current methods for detecting T cell responses to pathogens like SARS-CoV-2 are labor-intensive and difficult to scale.
• T cell receptors (TCRs) recognizing the same epitope often share similar sequences, suggesting TCR repertoire analysis can identify dominant immune responses.

Purpose of the Study:

• To identify public CD4+ T cell responses to SARS-CoV-2 using a meta-analysis of TCR datasets.
• To demonstrate the utility of a reverse epitope discovery approach based on TCR sequence similarity.

Main Methods:

• Performed a meta-analysis of publicly available single-cell and bulk TCR sequencing data from individuals infected with SARS-CoV-2.
• Identified clusters of similar TCR sequences to predict immunodominant responses.
• Validated HLA restriction and epitope specificity predictions using transgenic T cell lines.

Main Results:

• Identified over 1,200 αβTCRs forming six prominent similarity clusters associated with SARS-CoV-2 infection.
• Successfully validated HLA restriction and epitope specificity for five of these clusters.
• Demonstrated that TCR sequence similarity clusters effectively identify public T cell responses.

Conclusions:

• This study provides valuable insights into immunodominant CD4+ T cell responses to SARS-CoV-2.
• The reverse epitope discovery approach using TCR repertoire analysis is an efficient method for identifying pathogen-specific T cell responses.