Quantification of T-Cell and B-Cell Replication History in Aging, Immunodeficiency, and Newborn Screening

Quantification of T-cell receptor excision circles (TRECs) has impacted on human T-cell research, but interpretations on T-cell replication have been limited due to the lack of a genomic coding joint. We here overcome this limitation with multiplex TRG rearrangement quantification (detecting ~0.98 alleles per TCRαβ+ T cell) and the HSB-2 cell line with a retrovirally introduced TREC construct. We uncovered <5 cell divisions in naive and >10 cell divisions in effector memory T-cell subsets. Furthermore, we show that TREC dilution with age in healthy adults results mainly from increased T cell replication history. This proliferation was significantly increased in patients with predominantly antibody deficiency. Finally, Guthrie cards of neonates with Down syndrome have fewer T and B cells than controls, with similar T-cell and slightly higher B-cell replication. Thus, combined analysis of TRG coding joints and TREC signal joints can be utilized to quantify in vivo T-cell replication, and has direct applications for research into aging, immunodeficiency, and newborn screening.

• Publication year

  2019

• Venue

  Frontiers in Immunology

• Publication date

  2019-08-29

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3389/fimmu.2019.02084PMID 31543882PMCID 6730487
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Functional Antibody Responses Following Allogeneic Stem Cell Transplantation for TP53 Mutant pre-B-ALL in a Patient With X-Linked Agammaglobulinemia

  2019cited by this paper
• Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults

  2018cited by this paper
• Current best estimates for the average lifespans of mouse and human leukocytes: reviewing two decades of deuterium‐labeling experiments

  2018cited by this paper
• Newborn Screening for Severe Combined Immunodeficiency

  2018cited by this paper
• Global report on primary immunodeficiencies: 2018 update from the Jeffrey Modell Centers Network on disease classification, regional trends, treatment modalities, and physician reported outcomes

  2018cited by this paper
• Short Lifespans of Memory T-cells in Bone Marrow, Blood, and Lymph Nodes Suggest That T-cell Memory Is Maintained by Continuous Self-Renewal of Recirculating Cells

  2018cited by this paper
• International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity

  2017cited by this paper
• Newborn Screening for Primary Immunodeficiency Diseases: History, Current and Future Practice

  2017cited by this paper
• Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases.

  2017cited by this paper
• Flow cytometric analysis of T lymphocyte proliferation in vivo by EdU incorporation.

  2016cited by this paper
• The IL-23–IL-17 axis in inflammatory arthritis

  2015cited by this paper
• Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States

  2015cited by this paper
• Severe combined immunodeficiency—an update

  2015cited by this paper
• Persistent polyclonal B-cell lymphocytosis: extensively proliferated CD27+IgM+IgD+ memory B cells with a distinctive immunophenotype

  2014cited by this paper
• Retrospective Analysis of TREC Based Newborn Screening Results and Clinical Phenotypes in Infants with the 22q11 Deletion Syndrome

  2014cited by this paper
• Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States.

  2014cited by this paper
• Impact of Down syndrome on the performance of neonatal screening assays for severe primary immunodeficiency diseases.

  2014cited by this paper
• Combined TCRG and TCRA TREC analysis reveals increased peripheral T-lymphocyte but constant intra-thymic proliferative history upon ageing.

  2013cited by this paper
• Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin κ-deleting recombination excision circles.

  2013cited by this paper
• Increased circulating apoptotic lymphocytes in children with Down syndrome

  2012cited by this paper
• Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR.

  2012cited by this paper
• Morbidity and mortality in common variable immune deficiency over 4 decades.

  2012cited by this paper
• T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections

  2012cited by this paper
• Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways.

  2011cited by this paper
• B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency.

  2011influential reference
• Both Normal Memory Counts and Decreased Naive Cells Favor Intrinsic Defect Over Early Senescence of Down Syndrome T Lymphocytes

  2010cited by this paper
• Estimating human age from T-cell DNA rearrangements.

  2010cited by this paper
• Down Syndrome B-Lymphocyte Subpopulations, Intrinsic Defect or Decreased T-Lymphocyte Help

  2010cited by this paper
• The Use of Carboxyfluorescein Diacetate Succinimidyl Ester (CFSE) to Monitor Lymphocyte Proliferation

  2010cited by this paper
• Human CD4+ T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function

  2009cited by this paper
• Common variable immunodeficiency disorders: division into distinct clinical phenotypes.

  2008cited by this paper
• Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion

  2007influential reference
• Human T-cell lines with well-defined T-cell receptor gene rearrangements as controls for the BIOMED-2 multiplex polymerase chain reaction tubes

  2007cited by this paper
• Combined decrease of defined B and T cell subsets in a group of common variable immunodeficiency patients.

  2006cited by this paper
• Development of population-based newborn screening for severe combined immunodeficiency.

  2005influential reference
• New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling

  2005influential reference
• HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation.

  2004cited by this paper
• Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936

  2003cited by this paper
• Essential roles of the κ light chain intronic enhancer and 3′ enhancer in κ rearrangement and demethylation

  2002cited by this paper
• Essential roles of the kappa light chain intronic enhancer and 3' enhancer in kappa rearrangement and demethylation.

  2002cited by this paper
• Two Subsets of Naive T Helper Cells with Distinct T Cell Receptor Excision Circle Content in Human Adult Peripheral Blood

  2002cited by this paper
• T cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation

  2001cited by this paper
• Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection

  2000cited by this paper
• Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution.

  2000cited by this paper
• Quantitation of DNA extracted after micropreparation of cells from frozen and formalin-fixed tissue sections.

  2000cited by this paper
• Measurement of T-cell kinetics: recent methodologic advances.

  1999cited by this paper
• Functional analysis of peripheral blood B cells in patients with X-linked agammaglobulinemia.

  1998cited by this paper
• Changes in thymic function with age and during the treatment of HIV infection

  1998cited by this paper
• Preferential rearrangements of the T cell receptor-delta-deleting elements in human T cells.

  1997cited by this paper
• The Aging Immune System: Primer and Prospectus

  1996cited by this paper
• Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells.

  1994cited by this paper
• Lymphocyte life-span and memory.

  1994cited by this paper
• Parameters of the human genome.

  1991cited by this paper
• Analysis of immunoglobulin and T cell receptor genes. Part II: Possibilities and limitations in the diagnosis and management of lymphoproliferative diseases and related disorders.

  1991cited by this paper
• A uniform deleting element mediates the loss of kappa genes in human B cells.

  1985cited by this paper
• A uniform deleting element mediates the loss of κ genes in human B cells

  1985cited by this paper
• Small circular DNA complexes in eucaryotic cells.

  1982cited by this paper
• Establishment and characteristics of two unique cell lines from patients with lymphosarcoma

  1974cited by this paper
• Direct implantation and serial transplantation of human acute lymphoblastic leukemia in hamsters, SB-2.

  1968cited by this paper
• Immune deficiencies , infection , and systemic immune disorders Defective B-cell memory in patients with Down syndrome

  year unknowncited by this paper

• Impaired thymic function is independently associated with an increased risk of post-transplant infections in kidney recipients.

  2026cites this paper
• Utility of simultaneous quantification of TREC/KREC in patients with common variable immunodeficiency phenotype: an observational study from North India

  2025cites this paper
• Diverging effects of tumor necrosis factor inhibitors and conventional synthetic disease-modifying antirheumatic drugs on immunosenescence and inflammageing in rheumatoid arthritis: a cross-sectional analysis

  2025cites this paper
• Immune subset-committed proliferating cells populate the human foetal intestine throughout the second trimester of gestation

  2023cites this paper
• Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants.

  2023cites this paper
• B cell repertoire in patients with a novel BTK mutation: expanding the spectrum of atypical X-linked agammaglobulinemia

  2022cites this paper
• Immunosenescence and Autoimmunity: Exploiting the T-Cell Receptor Repertoire to Investigate the Impact of Aging on Multiple Sclerosis

  2021cites this paper
• Influenza‐specific IgG1+ memory B‐cell numbers increase upon booster vaccination in healthy adults but not in patients with predominantly antibody deficiency

  2020cites this paper
• Influenza-specific IgG1 + memory B-cell numbers increase upon booster vaccination in healthy adults but not in patients with predominantly antibody deficiency

  2020cites this paper
• Application of Cytometry in Primary Immunodeficiencies

  2020cites this paper
• Factors associated with immunosenescence during early adulthood in HIV-infected patients after durable efficient combination antiretroviral therapy

  2020cites this paper
• Inborn Errors of Adaptive Immunity in Down Syndrome

  2020cites this paper
• Early ART in Acute HIV-1 Infection: Impact on the B-Cell Compartment

  2020cites this paper
• Establishing Simultaneous T Cell Receptor Excision Circles (TREC) and K-Deleting Recombination Excision Circles (KREC) Quantification Assays and Laboratory Reference Intervals in Healthy Individuals of Different Age Groups in Hong Kong

  2020cites this paper
• Age-Related Lymphocyte Output During Disease-Modifying Therapies for Multiple Sclerosis

  2020cites this paper
• Functional Confirmation of DNA Repair Defect in Ataxia Telangiectasia (AT) Infants Identified by Newborn Screening for Severe Combined Immunodeficiency (NBS SCID).

  2020cites this paper
• Predominantly Antibody-Deficient Patients With Non-infectious Complications Have Reduced Naive B, Treg, Th17, and Tfh17 Cells

  2019cites this paper