These available repertoires are dramatically modified during antigen-driven responses especially in the inflammatory context of pathogen infections, autoimmune syndromes, and cancer to shape actual repertoires. In addition, several different functional T and B cells subsets have been identified, with differential dynamics and antigen-specific patterns. Primary IG and TR repertoires are therefore shaped to generate the available peripheral or mucosal repertoires.

During their differentiation, lymphocytes are subjected to selective processes, which lead to deletion of most auto-reactive cells, selection, export, and expansion, of mature T and B cells to the periphery. The product of the V-(D)-J joining, called the complementarity determining region 3 (CDR3) and corresponding to the signature of the rearrangement, binds the antigen and is responsible for the specificity of the recognition. TR and IG are produced by random somatic rearrangements of V, D, and J genes during lymphocyte differentiation. The resources available to generate the potential repertoires are described by the genomic T cell receptor (TR) and immunoglobulin (IG) loci. T and B cell repertoires are collections of lymphocytes, each characterized by its antigen-specific receptor. To conclude, we provide some examples of recent mathematical modeling strategies and perspectives that illustrate the active rise of a “next-generation” of repertoire analysis. We then present the variety of available statistical analysis and modeling approaches developed with regards to the various levels of diversity analysis, and reveal the increasing sophistication of those modeling approaches. In this line, we discuss the recent efforts made for nomenclature standardization and ontology development. NGS provides several angles of analysis such as clonotype frequency, CDR3 diversity, CDR3 sequence analysis, V allele identification with a quantitative dimension, therefore requiring high-throughput analysis tools development. Additionally, we introduce the recent technological advances in molecular biology tools allowing deeper analysis of IG/TR diversity by next-generation sequencing (NGS), offering systematic and comprehensive sequencing of IG/TR transcripts in a short amount of time. First, we describe the broad range of available methodological tools developed in the past decades, each of which answering different questions and showing complementarity for progressive identification of the level of repertoire alterations: global overview of the diversity by flow cytometry, IG repertoire descriptions at the protein level for the identification of IG reactivities, IG/TR CDR3 spectratyping strategies, and related molecular quantification or dynamics of T/B cell differentiation. We review here classical technologies and analysis strategies developed to assess immunoglobulin (IG) and T cell receptor (TR) repertoire diversity, and describe recent advances in the field. Analysis of the CDR3 length diversity within CD45RA and CD45RO T cells provides a more accurate measure of disturbances in the TCR repertoire than analysis of unfractionated CD4 and CD8 T cells.T and B cell repertoires are collections of lymphocytes, each characterized by its antigen-specific receptor. Sequence analysis of predominant CDR3 lengths revealed oligoclonal expansion within individual Vβ families. These differences were not apparent in unfractionated CD4 + or CD8 + T cells from HIV-infected subjects. Sharp differences in clonal dominance and size distributions were observed when cells were separated into CD45RA or CD45RO subpopulations. In contrast, HIV-infected children had a high proportion of predominant CDR3 lengths within both CD45RA and CD45RO T-cell subpopulations, most commonly in CD8 + CD45RO T cells. All T-cell subsets from newborn and healthy children demonstrated a Gaussian distribution of CDR3 lengths in separated T-cell subsets. Umbilical cord blood mononuclear cells or peripheral blood mononuclear cells obtained from healthy newborns, infants, and children, as well as human immunodeficiency virus (HIV)-infected children, were analyzed. By using PCR-based spectratyping, nested primers for all 24 human Vβ families were developed to amplify CDR3 lengths in immunomagnetically selected CD45RA and CD45RO subsets within both CD4 + and CD8 + T-cell populations. We hypothesized that CDR3 length diversity could be used to assess the fundamental differences within the TCR repertoire of CD45RA and CD45RO T-cell subpopulations. The T-cell receptor (TCR) CDR3 length heterogeneity is formed during recombination of individual Vβ gene families.

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