Integrated Modeling of BCR/TCR Repertoire Diversity Reveals the Mechanistic Basis of Immune Imprinting and Chronic Infection Control

The adaptive immune system orchestrates a complex interplay between humoral and cellular responses to resolve pathogen invasion and suppress tumorigenesis [1,91]. However, a unified quantitative framework integrating lymphocyte repertoire diversity with system-level kinetics remains elusive. Here, we present a multi-scale mathematical model that explicitly incorporates B-cell receptor (BCR) and T-cell receptor (TCR) clonotypic diversity into a discrete agent-based simulation. This framework mechanistically elucidates pivotal immunological phenomena, including the affinity-dependent selection in germinal centers [25], the kinetic constraints of immune imprinting ("original antigenic sin") [54], and the bifurcation between acute and chronic infection trajectories [15,59]. We identify that chronic infections are sustained by specific kinetic thresholds of viral replication relative to antibody affinity maturation. Furthermore, our simulations of cancer-immune interactions demonstrate that therapeutic efficacy is non-linearly dependent on neoantigen presentation [78] and T-cell exhaustion thresholds [79]. This work bridges the gap between reductionist data and systems biology, providing a "quantitative immunology" platform to optimize vaccine dosing schedules and design precision immunotherapies.