Longitudinal single-cell lineage mapping reveals TCR motifs shape CD8+ T cell fate and expansion 2310264

Abstract

Abstract Introduction When a naïve CD8+ T cell encounters a viral antigen from an acute infection, it undergoes cellular proliferation produce descendants with identical T cell receptors (TCRs), termed clones. These clones expand during an effector phase to clear the virus, then contract before forming a stable memory population. While cellular differentiation toward effector or memory fates occurs within clones, it remains unclear whether this process is stochastic or TCR-dependent. Due to the vast diversity of TCRs and the difficulty of tracing individual clones within a naturally arising repertoire, how clones dynamically progress throughout an acute infection remains unknown. Methods Using single-cell RNA/TCR sequencing in an LCMV Armstrong model of acute viral infection, 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 throughout infection. We then applied the TCRdist algorithm, which groups complementarity-determining region 3 (CDR3) into TCR motifs based on amino acid sequence similarity. Results We traced hundreds of clones and found that memory T cell clonal distribution is surprisingly not congruent with their early clonal dominance. Instead, we find that early central memory precursor frequency predicts memory clonal dominance. These analyses revealed that TCR sequence not only determines antigen specificity, but also influences proliferation and fate decisions during the immune response. Conclusion Overall, our findings provide novel insights into the evolution of a full polyclonal repertoire during acute viral infection, and uncovers a previously under-appreciated role for the TCR itself in shaping clonal expansion and differentiation. Funding Source n/a Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)