title: Immune dysregulation in immunodeficiency disorders: The role of T-cell receptor sequencing.
abstract: Immune dysregulation is a prominent feature of primary immunodeficiency disorders, which commonly manifested as autoimmunity, cytopenias and inflammatory bowel disease. In partial T-cell immunodeficiency disorders, it has been proposed that the imbalance between effector and regulatory T-cells drives the breakdown of peripheral tolerance. While there is no robust test for immune dysregulation, the T-cell receptor repertoire is used as a surrogate marker, and has been shown to be perturbed in a number of immunodeficiency disorders featuring immune dysregulation including Omenn's Syndrome, Wiskott-Aldrich Syndrome, and common variable immunodeficiency. This review discusses how recent advances in TCR next-generation sequencing and bioinformatics have led to the in-depth characterization of CDR3 sequences and an exponential growth in examinable parameters. Specifically, we highlight the use of junctional diversity as a means to differentiate intrinsic T-cell defects from secondary causes of repertoire perturbation in primary immunodeficiency disorders. However, key questions, such as the identity of antigenic targets for large, expanded T-cell clonotypes, remain unanswered despite the fact that such clones are likely to play a pathogenic role in driving immune dysregulation and autoimmunity. Finally, we discuss a number of emerging technologies such as in silico reconstruction, high-throughput pairwise αβ sequencing and single-cell RNAseq that offer the potential to define the antigenic epitope and function of a given T-cell, thereby enhancing our understanding in this field.
authors.affiliation: Institute of Immunology and Immunontherapy, Medical School, University of Birmingham, Edgbaston, B15 2TT, UK; UCB Pharma, Slough, Berkshire, SL1 3WE, UK.
authors.forename: Gabriel K
authors.initials: GK
authors.lastname: Wong
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine Harvard Medical School, 13th Street, Charlestown, MA, 02129, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Heather
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine Harvard Medical School, 13th Street, Charlestown, MA, 02129, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Barmettler
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine Harvard Medical School, 13th Street, Charlestown, MA, 02129, USA. Electronic address: mcobbold@mgh.harvard.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Cobbold
mesh_terms: D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D002999:Clone Cells; D019295:Computational Biology; D018604:Epitope Mapping; D059014:High-Throughput Nucleotide Sequencing; D006706:Homeostasis; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D059010:Single-Cell Analysis; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D011948:Receptors, Antigen, T-Cell
keywords: High throughput sequencing; Immune dysregulation; Immunodeficiency; Repertoire diversity; T-cell receptor