Unravelling T Cell Recognition

Reverse Epitope Discovery Using Deep Paired TCR Repertoire Sequencing

The enormous diversity of the T-cell receptor (TCR) repertoire allows our immune system to recognise a vast range of antigens. But looking at a TCR sequence alone, one of the hardest questions remains: what does this T cell actually recognise?

In this episode of Unravelling T Cell Recognition: Insights from Immunology and AI, Dr Mikhail (Misha) Pogorelyy, Director of Computational Sciences at Fred Hutch Cancer Center, discusses a different way of approaching this challenge: reverse epitope discovery.

The conversation centres on TIRTL-Seq, a strategy that combines the scale and affordability of bulk TCR repertoire sequencing with paired α/β TCR information. Misha explains how the approach works, why retaining TCR pairing matters, and how longitudinal sampling and computational analysis can help identify antigen-responsive T-cell clones.

We also explore the bigger question: can approaches like this eventually allow us to map TCR–antigen specificity at much greater scale? The discussion covers applications ranging from cancer immunotherapy to infectious disease, as well as the experimental and computational challenges that still need to be solved.

Watch the full webinar to hear Misha explain the method, its validation and where he thinks the field is heading.

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