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

Anastasia A Minervina,Elisa Rosati,Vadim K Karnaukhov,Ekaterina A Komech,Aleksandra M Walczak,Petra Bacher,Yuri B Lebedev,Andre Franke,Ilgar Z Mamedov,Thierry Mora,Dmitriy M Chudakov,Mikhail V Pogorelyy

doi:10.7554/elife.53704

Abstract

The diverse repertoire of T-cell receptors (TCR) plays a key role in the adaptive immune response to infections. 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 - the model for acute infection in humans - showing their large diversity. We confirm the secondary response is an order of magnitude weaker, albeit ∼10 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.

Highlights

T-cells play a crucial role in the immune response to pathogens by mediating antibody formation and clearance of infected cells, and by defining an overall response strategy
The biological replicates of bulk peripheral blood mononuclear cells (PBMCs) were used to estimate the noise in the T-cell receptors (TCR) mRNA counts
Overall we found 1580 TCR beta and 1566 TCR alpha clonotypes significantly expanded after the primary immunization, respectively occupying 6.7% and 7.8% of the sampled TCR repertoire of bulk PBMCs in cumulative frequency at the peak of the response (Figure 1B,C)

Summary

Introduction

T-cells play a crucial role in the immune response to pathogens by mediating antibody formation and clearance of infected cells, and by defining an overall response strategy. The specificity of T-cells is determined by the T-cell receptor (TCR), a heterodimer of alpha and beta protein chains. Genes for alpha and beta chains assemble in a random process of somatic V(D)J-recombination, which leads to a huge variety of possible TCRs (Murugan et al, 2012). The resulting diverse naıve repertoire contains T-cell clones that recognize epitopes of yet unseen pathogens, and can participate in the immune response to infection or vaccination. One of the best established models of acute viral infection in humans is yellow fever (YF) vaccination. The dynamics of primary T-cell response was investigated by various

Methods

Results

Conclusion