ClonoDeconv: reference-based α - β paired recurrent clonotype proportion estimation from bulk-TCR sequencing

Abstract

T cell receptor (TCR) sequencing is crucial when studying antigen-specific T cell responses and clonal dynamics. A key objective of TCR repertoire analysis is to identify recurring clonotypes across timepoints or different disease states, providing insight into the evolution of immune response. Bulk-TCR sequencing enables high-throughput profiling of TCR and {beta} sequences but lacks pairing information, while single cell TCR sequencing (scTCR-seq) retains pairing information but is limited by sensitivity, throughput, and costs. We present ClonoDeconv, a computational framework to deconvolute paired TCR {beta} ; clonotype frequency from bulk TCR sequencing experiments using a paired scTCR-seq reference. ClonoDeconv robustly estimated shared clonotype abundances from 5' RACE bulk-TCR datasets using a scTCR-seq reference from the same donor. Applied to longitudinal samples, ClonoDeonv successfully captured the expansion and contraction of rare virus-specific clones across timepoints. Taken together, ClonoDeconv provides a cost-effective and scalable approach for studying the longitudinal T-cell clonal dynamics.