Xiaomin Yu1, Jorge R Almeida2, Sam Darko2, Mirjam van der Burg3, Suk See DeRavin4, Harry Malech4, Andrew Gennery5, Ivan Chinn6, Mary Louise Markert7, Daniel C Douek8, Joshua D Milner9. 1. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 2. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 3. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 4. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 5. Department of Paediatric Immunology, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. 6. Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC. 7. Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC; Department of Immunology, Duke University Medical Center, Durham, NC. 8. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: ddouek@mail.nih.gov. 9. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: jdmilner@niaid.nih.gov.
Abstract
BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Published by Mosby, Inc.
BACKGROUND:Humanimmunodeficiencies 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Published by Mosby, Inc.
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