Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development
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 c...
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| Published in | Journal of allergy and clinical immunology Vol. 133; no. 4; pp. 1109 - 1115.e14 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York, NY
Elsevier Inc
01.04.2014
Elsevier Elsevier Limited |
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| Abstract | 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. |
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| AbstractList | 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. 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. 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 TCR beta complementarity-determining region 3 (CDR3) regions in subjects with a series of immune dysregulatory conditions caused by mutations in recombination activating gene 1/2 , IL-2 receptor gamma , and zeta chain-associated protein kinase 70 ; a patient with atypical DiGeorge syndrome; and healthy control subjects. Results We found that patients with OS had marked reductions in TCR beta diversity compared with control subjects, as expected. Patients with atypical presentations of or 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. TCR beta from patients with 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. 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.BACKGROUNDHuman 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.OBJECTIVEThe 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.METHODSWe 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.RESULTSWe 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.CONCLUSIONSHigh-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. 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. 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 ofRAGorIL2RGmutations 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 withRAGmutations 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. |
| Author | Douek, Daniel C. Yu, Xiaomin Almeida, Jorge R. Darko, Sam van der Burg, Mirjam Gennery, Andrew Malech, Harry Milner, Joshua D. DeRavin, Suk See Markert, Mary Louise Chinn, Ivan |
| AuthorAffiliation | e Department of Paediatric Immunology, New-castle University, Newcastle upon Tyne a Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda b Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda g Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham h Department of Immunology, Duke University Medical Center, Durham d Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda c Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam f Institute of Cellular Medicine, New-castle University, Newcastle upon Tyne |
| AuthorAffiliation_xml | – name: c Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam – name: e Department of Paediatric Immunology, New-castle University, Newcastle upon Tyne – name: g Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham – name: f Institute of Cellular Medicine, New-castle University, Newcastle upon Tyne – name: b Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda – name: h Department of Immunology, Duke University Medical Center, Durham – name: a Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda – name: d Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda |
| Author_xml | – sequence: 1 givenname: Xiaomin surname: Yu fullname: Yu, Xiaomin organization: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md – sequence: 2 givenname: Jorge R. surname: Almeida fullname: Almeida, Jorge R. organization: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md – sequence: 3 givenname: Sam surname: Darko fullname: Darko, Sam organization: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md – sequence: 4 givenname: Mirjam surname: van der Burg fullname: van der Burg, Mirjam organization: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands – sequence: 5 givenname: Suk See surname: DeRavin fullname: DeRavin, Suk See organization: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md – sequence: 6 givenname: Harry surname: Malech fullname: Malech, Harry organization: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md – sequence: 7 givenname: Andrew surname: Gennery fullname: Gennery, Andrew organization: Department of Paediatric Immunology, Newcastle University, Newcastle upon Tyne, United Kingdom – sequence: 8 givenname: Ivan surname: Chinn fullname: Chinn, Ivan organization: Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC – sequence: 9 givenname: Mary Louise surname: Markert fullname: Markert, Mary Louise organization: Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC – sequence: 10 givenname: Daniel C. surname: Douek fullname: Douek, Daniel C. email: ddouek@mail.nih.gov organization: Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md – sequence: 11 givenname: Joshua D. surname: Milner fullname: Milner, Joshua D. email: jdmilner@niaid.nih.gov organization: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md |
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| Keywords | 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 |
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| Snippet | Human immunodeficiencies characterized by hypomorphic mutations in critical developmental and signaling pathway genes allow for the dissection of the role of... Background Human immunodeficiencies characterized by hypomorphic mutations in critical developmental and signaling pathway genes allow for the dissection of... Background: Human immunodeficiencies characterized by hypomorphic mutations in critical developmental and signaling pathway genes allow for the dissection of... |
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| SubjectTerms | 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 |
| Title | Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development |
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