Longitudinal single-cell lineage mapping of a tetramer-specific CD8+ T cell repertoire during an acute infection 4481

Abstract Description When a naïve CD8+ T cell encounters an epitope, it divides into clones with identical T cell receptors (TCRs). These clones expand during an effector phase to clear the virus, then contract before forming a stable memory population. Clonal bias toward effector or memory subtypes occurs, but it’s unclear if this is stochastic or TCR-dependent. Due to the vast diversity of the TCRs and the difficulty of tracing individual clonal lineages within a polyclonal repertoire, how clones dynamically progress throughout an acute infection remains unknown. Using single-cell RNA and TCR sequencing in an acute LCMV Armstrong model, we showed that clonal distributions in blood reflect those in spleen and lymph nodes. This enables non-lethal blood sampling for longitudinal tracking of clonal evolution during infection. We traced 1000s of naïve cell descendants and found that early clonal dominance weakly predicts memory clonal dominance. On the other hand, we find that early central memory precursor frequency predicts memory clonal dominance. Finally, using TCRdist algorithm on our scTCR-seq data, we characterize CDR3 into district categorizations based on amino acid sequence similarity we call motifs. Our results suggest that TCR sequence is critical not only for antigen specificity, but also for determining cell fate choice and expansion. Overall, our results provide a first look into the dynamics of an entire polyclonal repertoire across an acute infection. Topic Categories Viral Immunology (VIR)