Lossius a immune repertoire6/23/2023 (B) Analysis of repertoire architecture relies predominantly on (i) clonal networks that are constructed by connecting nucleotide or amino acid sequence nodes by similarity edges. (iii) Measurement of clonotype diversity using diversity profiles. (ii) Probabilistic and hidden Markov models allow inference of recombination statistics. (A) Diversity measurements are based on (i) the accurate annotation of V (D) J segments using deterministic and probabilistic approaches with population-level or individualized germline gene reference databases. The immune repertoire space is defined by diversity, architecture, evolution, and convergence. To date, the computational methods that have been developed and applied to immune repertoires relate to (i) the underlying mechanisms of diversity generation, (ii) repertoire architecture, (iii) antibody evolution, and (iv) molecular convergence.įigure 1. Immune repertoire sequencing has catalyzed the field of computational and systems immunology in the same way that genomics and transcriptomics have for systems and computational biology ( 23). The exponential rise in immune repertoire data has correspondingly led to a large increase in the number of computational methods directed at dissecting repertoire complexity (Figures 1 and 2) ( 23). Since 2009, high-throughput adaptive immune receptor repertoire sequencing (AIRR-seq) has provided unprecedented molecular insight into the complexity of adaptive immunity by generating data sets of 100 millions to billions of reads ( 6, 21, 22). The quantitative resolution of immune repertoires has been fueled by the advent of high-throughput sequencing ( 2, 15– 20). Repertoire dynamics and evolution span several orders of magnitude in size (germline gene to clonal diversity), physical components (molecular to cellular dynamics), and time (short-lived responses to immunological memory that can persist for decades) ( 9– 14). They are constantly evolving within the repertoire sequence space, which is defined as the set of all biologically achievable immune receptor sequences. Current threats, for example of pathogenic nature, are countered by B- and T-cell clonal expansion and selection ( 7), whereas past ones are archived in immunological memory compartments ( 8). The adaptive immune repertoire often refers to the collection of all antibody and T-cell immune receptors within an individual and represents both the ongoing and the past immune status of an individual. 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.
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