Nonequilibrium Antigen Recognition during Infections and Vaccinations

Le résumé fourni par la source

The initial immune response to an acute primary infection is a coupled process of antigen proliferation, molecular recognition by naive B cells, and their subsequent clonal expansion. This process contains a fundamental problem: the recognition of an exponentially time-dependent antigen signal. Here, we show that an efficient immune response must be stringently constrained to B-cell lineages with high antigen binding affinity. We propose a tuned proofreading mechanism for primary recognition of new antigens, where the molecular recognition machinery is adapted to the complexity of the immune repertoire. We show that this process produces potent, specific, and fast recognition of antigens, maintaining a spectrum of genetically distinct B-cell lineages as input for affinity maturation. Our analysis maps the proliferation-recognition dynamics of a primary infection to a generalized Luria-Delbrück process, akin to the dynamics of the classic fluctuation experiment. This map establishes a link between signal recognition dynamics and evolution. We derive the resulting statistics of the activated immune repertoire: Antigen binding affinity, expected size, and frequency of active B-cell clones are related by power laws, which define the class of generalized Luria-Delbrück processes. Their exponents depend on the antigen and B-cell proliferation rate, the number of proofreading steps, and the lineage density of the naive repertoire. We extend the model to include spatiotemporal processes, including the diffusion-recognition dynamics of a vaccination. Empirical data of activated mouse immune repertoires are found to be consistent with activation involving about three proofreading steps. The model predicts key clinical characteristics of acute infections and vaccinations, including the emergence of elite neutralizers and the effects of immune aging. More broadly, our results establish infections and vaccinations as a new probe into the global architecture and functional principles of immune repertoires. Published by the American Physical Society 2024

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.