Primary and secondary anti-viral response captured by the dynamics and phenotype of individual T cell clones

TL;DR

This study tracks individual T-cell clone dynamics and phenotypes during primary and secondary yellow fever responses, revealing differences in strength, speed, and TCR features that underpin immune memory.

Contribution

It introduces a comprehensive approach combining TCR sequencing and single-cell RNAseq to analyze T-cell clone behavior and TCR features in primary and secondary immune responses.

Findings

Secondary response is ~10 times weaker but faster by ~10 days.

Identified TCR sequence motifs linked to high precursor frequency.

Reconstructed alpha-beta TCR pairings from clonal trajectories.

Abstract

The diverse repertoire of T-cell receptors (TCR) plays a key role in the adaptive immune response to infections. Previous studies show that secondary responses to the yellow fever vaccine - the model for acute infection in humans - are weaker than primary ones, but only quantitative measurements can describe the concentration changes and lineage fates for distinct T-cell clones in vivo over time. Using TCR alpha and beta repertoire sequencing for T-cell subsets, as well as single-cell RNAseq and TCRseq, we track the concentrations and phenotypes of individual T-cell clones in response to primary and secondary yellow fever immunization showing their large diversity. We confirm the secondary response is an order of magnitude weaker, albeit $\sim10$ days faster than the primary one. Estimating the fraction of the T-cell response directed against the single immunodominant epitope, we identify the sequence features of TCRs that define the high precursor frequency of the two major TCR motifs specific for this particular epitope. We also show the consistency of clonal expansion dynamics between bulk alpha and beta repertoires, using a new methodology to reconstruct alpha-beta pairings from clonal trajectories.