![]() ![]() During the gene rearrangement process, additional sequence diversity is created by nucleotide deletion and addition, resulting in a potential diversity of >10 13 unique B- and T-cell immune receptor sequences ( 3– 6). The genetic diversity of these adaptive immune receptors is generated through a somatic recombination process that acts on their constituent V, D, and J segments ( 1, 2). Molecular recognition of antigens is achieved through the vast diversity of antibody (B-cell receptor) and T-cell receptors (TCRs). The adaptive immune system is responsible for the specific recognition and elimination of antigens originating from infection and disease. We summarize outstanding questions in computational immunology and propose future directions for systems immunology toward coupling AIRR-seq with the computational discovery of immunotherapeutics, vaccines, and immunodiagnostics. Here, we review the current research on (i) diversity, (ii) clustering and network, (iii) phylogenetic, and (iv) machine learning methods applied to dissect, quantify, and compare the architecture, evolution, and specificity of immune repertoires. Several methods for the computational and statistical analysis of large-scale AIRR-seq data have been developed to resolve immune repertoire complexity and to understand the dynamics of adaptive immunity. ![]() Adaptive immune receptor repertoire sequencing (AIRR-seq) has driven the quantitative and molecular-level profiling of immune repertoires, thereby revealing the high-dimensional complexity of the immune receptor sequence landscape. The interrogation of immune repertoires is of high relevance for understanding the adaptive immune response in disease and infection (e.g., autoimmunity, cancer, HIV). The adaptive immune system recognizes antigens via an immense array of antigen-binding antibodies and T-cell receptors, the immune repertoire. 5Department of Immunology, University of Oslo, Oslo, Norway.4Department of Internal Medicine, Clinical Immunology, University Hospital Basel, Basel, Switzerland.3Department of Biomedicine, University Hospital Basel, Basel, Switzerland.2aiNET GmbH, ETH Zürich, Basel, Switzerland.1Department for Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland. ![]()
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