title: The past, present, and future of immune repertoire biology - the rise of next-generation repertoire analysis.
abstract: T and B cell repertoires are collections of lymphocytes, each characterized by its antigen-specific receptor. 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. 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. 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. 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. In this line, we discuss the recent efforts made for nomenclature standardization and ontology development. 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. 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.
authors.affiliation: UPMC University Paris 06, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; AP-HP, Hôpital Pitié-Salpêtrière, CIC-BTi Biotherapy , Paris , France ; AP-HP, Hôpital Pitié-Salpêtrière, Département Hospitalo-Universitaire (DHU), Inflammation-Immunopathology-Biotherapy (i2B) , Paris , France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Six
authors.affiliation: UPMC University Paris 06, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; AP-HP, Hôpital Pitié-Salpêtrière, Département Hospitalo-Universitaire (DHU), Inflammation-Immunopathology-Biotherapy (i2B) , Paris , France.
authors.forename: Maria Encarnita
authors.initials: ME
authors.lastname: Mariotti-Ferrandiz
authors.affiliation: UPMC University Paris 06, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; AP-HP, Hôpital Pitié-Salpêtrière, CIC-BTi Biotherapy , Paris , France ; AP-HP, Hôpital Pitié-Salpêtrière, Département Hospitalo-Universitaire (DHU), Inflammation-Immunopathology-Biotherapy (i2B) , Paris , France.
authors.forename: Wahiba
authors.initials: W
authors.lastname: Chaara
authors.affiliation: Institut National de la Recherche Agronomique, Unité de Virologie et Immunologie Moléculaires , Jouy-en-Josas , France.
authors.forename: Susana
authors.initials: S
authors.lastname: Magadan
authors.affiliation: UPMC University Paris 06, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France.
authors.forename: Hang-Phuong
authors.initials: HP
authors.lastname: Pham
authors.affiliation: IMGT®, The International ImMunoGeneTics Information System®, Institut de Génétique Humaine, UPR CNRS 1142, Université Montpellier 2 , Montpellier , France.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Lefranc
authors.affiliation: Laboratoire de Physique Statistique, UMR8550, CNRS and Ecole Normale Supérieure , Paris , France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Mora
authors.affiliation: UPMC University Paris 06, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; CNRS, UMR 7211, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; INSERM, UMR_S 959, Immunology-Immunopathology-Immunotherapy (I3) , Paris , France ; AP-HP, Hôpital Pitié-Salpêtrière, Département Hospitalo-Universitaire (DHU), Inflammation-Immunopathology-Biotherapy (i2B) , Paris , France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Thomas-Vaslin
authors.affiliation: Laboratoire de Physique Théorique, UMR8549, CNRS and Ecole Normale Supérieure , Paris , France.
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Walczak
authors.affiliation: Institut National de la Recherche Agronomique, Unité de Virologie et Immunologie Moléculaires , Jouy-en-Josas , France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Boudinot
keywords: B cell repertoire; T cell repertoire; diversity analysis; gene nomenclature; immune receptors; modeling; next-generation sequencing; statistics