AUTHOR=Verstegen Ruud H. J. , Aui Pei M. , Watson Eliza , De Jong Samuel , Bartol Sophinus J. W. , Bosco Julian J. , Cameron Paul U. , Stirling Robert G. , de Vries Esther , van Dongen Jacques J. M. , van Zelm Menno C. TITLE=Quantification of T-Cell and B-Cell Replication History in Aging, Immunodeficiency, and Newborn Screening JOURNAL=Frontiers in Immunology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02084 DOI=10.3389/fimmu.2019.02084 ISSN=1664-3224 ABSTRACT=

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.