期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：34
DOI：10.1073/pnas.2203505119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
How can one measure the breadth of the adaptive immune system’s function, based on the amino acid sequences of its millions of constituent antibodies and T cell receptors (TCRs)? One approach has been to cluster sequences according to some ad hoc sequence similarity threshold and then count the resulting clusters. However, it would be more faithful to the basic function of antibodies and TCRs to group each pair based on how similar their epitope-binding properties are expected to be, and then integrate over the entire repertoire to estimate the effective number of unique targets the repertoire has the capacity to bind. Accordingly, we present a framework for repertoire-scale measurement of immunological diversity and several resulting insights in health and disease.
Antibodies and T cell receptors (TCRs) are the fundamental building blocks of adaptive immunity. Repertoire-scale functionality derives from their epitope-binding properties, just as macroscopic properties like temperature derive from microscopic molecular properties. However, most approaches to repertoire-scale measurement, including sequence diversity and entropy, are not based on antibody or TCR function in this way. Thus, they potentially overlook key features of immunological function. Here we present a framework that describes repertoires in terms of the epitope-binding properties of their constituent antibodies and TCRs, based on analysis of thousands of antibody–antigen and TCR–peptide–major-histocompatibility-complex binding interactions and over 400 high-throughput repertoires. We show that repertoires consist of loose overlapping classes of antibodies and TCRs with similar binding properties. We demonstrate the potential of this framework to distinguish specific responses vs. bystander activation in influenza vaccinees, stratify cytomegalovirus (CMV)-infected cohorts, and identify potential immunological “super-agers.” Classes add a valuable dimension to the assessment of immune function.
关键词：enB cell repertoiresT cell repertoiresimmunological diversityantigen bindingGibbs free energy
