Computational Biologist Massachusetts Gen. Hosp., United States
Introduction/Rationale: T-cells lie at the intersection of immune surveillance and therapy, acting as both indicators of immune activity (living biomarkers) and effectors of disease control (living drugs). Their T-cell receptors (TCRs) encode a molecular history of immune activation, yet large-scale, cross-disease mapping of TCR dynamics and T-cell states in blood remains unresolved.
Methods: Here, we leverage a single-cell immune atlas of 20 million peripheral blood mononuclear cells, including over 7 million CD4+ and CD8+ T-cells, paired with full-length TCR sequencing across 2,000 donors spanning 40+ immune-mediated, infectious, and immune checkpoint-related conditions. We also used arcasHLA with 10x scRNA-seq reads to call HLA genotypes on each patient sample to perform HLA association analysis.
Results: Preliminary findings recapitulate canonical antiviral expansions, while highlighting nuanced T-cell effector shifts in checkpoint-related toxicity and autoimmunity. By treating the TCR as a natural clonal barcode, we chart how T cells respond, adapt, and converge across diverse immune contexts. By coupling TCR diversity with HLA genotype, we uncover genetic determinants of clonal selection and immune activation, offering a framework to relate antigen presentation genetics to disease-specific T-cell responses. This work lays a foundation for discovering universal diagnostic signatures and informing next-generation cellular therapies, unlocking the clinical potential of TCRs as biomarkers and therapeutic targets in precision immunology.
Conclusion: The unprecedented scale of our atlas enables deep profiling of rare clonotypes and subtle, condition-specific expansions. We explore how clonality and transcriptional state intersect to reveal shared and disease-specific patterns of activation, exhaustion, and memory across circulating T cell subsets.
