Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 4; pp. 1109 - 1115.e14
• Main Authors: Yu, Xiaomin, Almeida, Jorge R., Darko, Sam, van der Burg, Mirjam, DeRavin, Suk See, Malech, Harry, Gennery, Andrew, Chinn, Ivan, Markert, Mary Louise, Douek, Daniel C., Milner, Joshua D.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.04.2014; Elsevier; Elsevier Limited
• Subjects: Allergy and Immunology; Amino Acid Substitution; Biological and medical sciences; Bone marrow; Case-Control Studies; Child; Child, Preschool; Complementarity Determining Regions - genetics; DNA-Binding Proteins - genetics; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Homeodomain Proteins - genetics; Humans; Immune system; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunopathology; Infant; Interleukin Receptor Common gamma Subunit - genetics; Kinases; Male; Medical sciences; Mutation; Nuclear Proteins - genetics; Omenn syndrome; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell, alpha-beta - genetics; recombination activating gene; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sequence Analysis, DNA; Severe Combined Immunodeficiency - genetics; T-cell receptor; T-cell receptor sequencing; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Viral infections; ZAP-70 Protein-Tyrosine Kinase - genetics; T-cell receptor; ZAP70; TCR; recombination activating gene; OS; TdT; RAG; IL2RG; Omenn syndrome; CDR3; SCID; T-cell receptor sequencing; Severe combined immunodeficiency; IL-2 receptor γ; ζ chain–associated protein kinase 70; Terminal deoxynucleotidyl transferase; Complementarity-determining region 3; Human; Immunopathology; Recombination; T cell receptor; Nucleotide sequence; Genetic disease; Immunology; Gene; T-Lymphocyte; Genetics; Immunologic repertoire; Sequencing
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2013.11.018

Human immunodeficiencies characterized by hypomorphic mutations in critical developmental and signaling pathway genes allow for the dissection of the role of these genes in the development of the T-cell receptor (TCR) repertoire and the correlation of alterations of the TCR repertoire with diverse clinical phenotypes. The presence of T cells in patients with Omenn syndrome (OS) and patients with atypical presentations of severe combined immunodeficiency gene mutations presents an opportunity to study the effects of the causal genes on TCR repertoires and provides a window into the clinical heterogeneity observed. We performed deep sequencing of TCRβ complementarity-determining region 3 (CDR3) regions in subjects with a series of immune dysregulatory conditions caused by mutations in recombination activating gene 1/2 (RAG 1/2), IL-2 receptor γ (IL2RG), and ζ chain–associated protein kinase 70 (ZAP70); a patient with atypical DiGeorge syndrome; and healthy control subjects. We found that patients with OS had marked reductions in TCRβ diversity compared with control subjects, as expected. Patients with atypical presentations of RAG or IL2RG mutations associated with autoimmunity and granulomatous disease did not have altered overall diversity but instead had skewed V-J pairing and skewed CDR3 amino acid use. Although germline TCRs were more abundant and clonally expanded in patients with OS, nongermline sequences were expanded as well. TCRβ from patients with RAG mutations had less junctional diversity and smaller CDR3s than patients with OS caused by other gene mutations and healthy control subjects but relatively similar CDR3 amino acid use. High-throughput TCR sequencing of rare immune disorders has demonstrated that quantitative TCR diversity can appear normal despite qualitative changes in repertoire and strongly suggests that in human subjects RAG enzymatic function might be necessary for normal CDR3 junctional diversity.