{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:57:17Z","timestamp":1771549037343,"version":"3.50.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011731","name":"Action for A-T","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Ataxia Telangiectasia (AT) is a rare inherited disorder characterized by progressive cerebellar ataxia, chromosomal instability, cancer susceptibility and immunodeficiency. AT is caused by mutations in the ATM gene, which is involved in multiple processes linked to DNA double strand break repair. Immunologically, ATM mutations lead to hampered V(D)J recombination and consequently reduced numbers of naive B and T cells. In addition, class switch recombination is disturbed resulting in antibody deficiency causing common, mostly sinopulmonary, bacterial infections. Yet, AT patients in general have no clinical T cell associated infections and numbers of memory T cells are usually normal. In this study we investigated the naive and memory T cell compartment in five patients with classical AT and compared them with five healthy controls using a 24-color antibody panel and spectral flow cytometry. Multidimensional analysis of CD4 and CD8 TCR\u03b1\u03b2<jats:sup>+<\/jats:sup> cells revealed that early naive T cell populations, i.e. CD4<jats:sup>+<\/jats:sup>CD31<jats:sup>+<\/jats:sup> recent thymic emigrants and CD8<jats:sup>+<\/jats:sup>CCR7<jats:sup>++<\/jats:sup>CD45RA<jats:sup>++<\/jats:sup> T cells, were strongly reduced in AT patients. However, we identified normal numbers of stem cell memory T cells expressing CD95, which are antigen-experienced T cells that can persist for decades because of their self-renewal capacity. We hypothesize that the presence of stem cell memory T cells explains why AT patients have an intact memory T cell compartment. In line with this novel finding, memory T cells of AT patients were normal in number and expressed chemokine receptors, activating and inhibitory receptors in comparable percentages as controls. Comparing memory T cell phenotypes by Boolean gating revealed similar diversity indices in AT compared to controls. We conclude that AT patients have a fully developed memory T cell compartment despite strongly reduced naive T cells. This could be explained by the presence of normal numbers of stem cell memory T cells in the naive T cell compartment, which support the maintenance of the memory T cells. The identification of stem cell memory T cells <jats:italic>via<\/jats:italic> our spectral flow cytometric approach is highly relevant for better understanding of T cell immunity in AT. Moreover, it provides possibilities for further research on this recently identified T cell population in other inborn errors of immunity.<\/jats:p>","DOI":"10.3389\/fimmu.2021.686333","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T08:43:37Z","timestamp":1624524217000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Normal Numbers of Stem Cell Memory T Cells Despite Strongly Reduced Naive T Cells Support Intact Memory T Cell Compartment in Ataxia Telangiectasia"],"prefix":"10.3389","volume":"12","author":[{"given":"Thomas J.","family":"Weitering","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janine E.","family":"Melsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monique M.","family":"van Ostaijen-ten Dam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corry M. R.","family":"Weemaes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco W.","family":"Schilham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirjam","family":"van der Burg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1186\/s13023-016-0543-7","article-title":"Ataxia Telangiectasia: A Review","volume":"11","author":"Rothblum-Oviatt","year":"2016","journal-title":"Orphanet J Rare Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2021.02.001","article-title":"Atm: Translating the DNA Damage Response to Adaptive Immunity","volume":"42","author":"Weitering","year":"2021","journal-title":"Trends Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-009-0408-0","article-title":"Phenotypic Variations Between Affected Siblings With Ataxia-Telangiectasia: Ataxia-Telangiectasia in Japan","volume":"90","author":"Morio","year":"2009","journal-title":"Int J Hematol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1076736","article-title":"Different Clinical and Immunological Presentation of Ataxia-Telangiectasia Within the Same Family","volume":"39","author":"Soresina","year":"2008","journal-title":"Neuropediatrics"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2003.12.046","article-title":"Immunodeficiency and Infections in Ataxia-Telangiectasia","volume":"144","author":"Nowak-Wegrzyn","year":"2004","journal-title":"J Pediatr"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2008.149351","article-title":"Ataxia-Telangiectasia Patients Presenting With hyper-IgM Syndrome","volume":"94","author":"Noordzij","year":"2009","journal-title":"Arch Dis Child"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nature04866","article-title":"ATM Stabilizes DNA Double-Strand-Break Complexes During V(D)J Recombination","volume":"442","author":"Bredemeyer","year":"2006","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nature09604","article-title":"ATM Damage Response and XLF Repair Factor are Functionally Redundant in Joining DNA Breaks","volume":"469","author":"Zha","year":"2011","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2732","article-title":"A DNA Break- and Phosphorylation-Dependent Positive Feedback Loop Promotes Immunoglobulin Class-Switch Recombination","volume":"14","author":"Vuong","year":"2013","journal-title":"Nat Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200205)32:5<1300::AID-IMMU1300>3.0.CO;2-L","article-title":"Alternative End Joining During Switch Recombination in Patients With Ataxia-Telangiectasia","volume":"32","author":"Pan","year":"2002","journal-title":"Eur J Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1016\/j.jaci.2013.01.053","article-title":"Antibody Deficiency in Patients With Ataxia Telangiectasia is Caused by Disturbed B- and T-cell Homeostasis and Reduced Immune Repertoire Diversity","volume":"131","author":"Driessen","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-03-0976","article-title":"Skewed T-cell Receptor Repertoire, Decreased Thymic Output, and Predominance of Terminally Differentiated T Cells in Ataxia Telangiectasia","volume":"100","author":"Giovannetti","year":"2002","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1007\/s10875-020-00881-9","article-title":"Variable Abnormalities in T and B Cell Subsets in Ataxia Telangiectasia","volume":"41","author":"Moeini Shad","year":"2021","journal-title":"J Clin Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(66)90080-5","article-title":"Lymphoid Tissue Abnormalities Associated With Ataxia-Telangiectasia","volume":"41","author":"Peterson","year":"1966","journal-title":"Am J Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.aller.2014.06.007","article-title":"Comparison of Major Lymphocyte Subpopulations and Recent Thymic Emigrants in Patients With Ataxia Telangiectasia and Age-Matched Healthy Groups","volume":"43","author":"Celiksoy","year":"2015","journal-title":"Allergol Immunopathol (Madr)"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-014-0044-1","article-title":"And T Cell Homeostasis and Neogenesis in Patients With Ataxia Telangiectasia","volume":"34","author":"Kraus","year":"2014","journal-title":"J Clin Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02438","article-title":"Dilemma of Reporting Incidental Findings in Newborn Screening Programs for SCID: Parents\u2019 Perspective on Ataxia Telangiectasia","volume":"10","author":"Blom","year":"2019","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00373","article-title":"Universal Newborn Screening for Severe Combined Immunodeficiency (Scid)","volume":"7","author":"van der Burg","year":"2019","journal-title":"Front Pediatr"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1901530","article-title":"A Comprehensive Workflow for Applying Single-Cell Clustering and Pseudotime Analysis to Flow Cytometry Data","volume":"205","author":"Melsen","year":"2020","journal-title":"J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw191","article-title":"flowAI: Automatic and Interactive Anomaly Discerning Tools for Flow Cytometry Data","volume":"32","author":"Monaco","year":"2016","journal-title":"Bioinformatics"},{"key":"B21","first-page":"1802.03426","article-title":"UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction","author":"McInnes","year":"2018","journal-title":"ArXiv e-prints"},{"key":"B22","doi-asserted-by":"publisher","first-page":"5415","DOI":"10.1038\/s41467-019-13055-y","article-title":"Automated Optimized Parameters for T-Distributed Stochastic Neighbor Embedding Improve Visualization and Analysis of Large Datasets","volume":"10","author":"Belkina","year":"2019","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","first-page":"57","DOI":"10.2307\/sysbio\/13.1-4.57","article-title":"Species Density of North American Recent Mammals","volume":"13","author":"Simpson","year":"1964","journal-title":"Syst Zool"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500703","article-title":"Phenotypic Complexity of the Human Regulatory T Cell Compartment Revealed by Mass Cytometry","volume":"195","author":"Mason","year":"2015","journal-title":"J Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0001-y","article-title":"The Full Spectrum of Human Naive T Cells","volume":"18","author":"van den Broek","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.3.754","article-title":"Differentiation of Cytomegalovirus-Specific CD8(+) T Cells in Healthy and Immunosuppressed Virus Carriers","volume":"98","author":"Gamadia","year":"2001","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nri1254","article-title":"Human CD8(+) T-Cell Differentiation in Response to Viruses","volume":"3","author":"van Lier","year":"2003","journal-title":"Nat Rev Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2446","article-title":"A Human Memory T Cell Subset With Stem Cell-Like Properties","volume":"17","author":"Gattinoni","year":"2011","journal-title":"Nat Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/nm.4241","article-title":"T Memory Stem Cells in Health and Disease","volume":"23","author":"Gattinoni","year":"2017","journal-title":"Nat Med"},{"key":"B30","doi-asserted-by":"publisher","first-page":"273ra13","DOI":"10.1126\/scitranslmed.3010314","article-title":"In\u00a0Vivo Tracking of T Cells in Humans Unveils Decade-Long Survival and Activity of Genetically Modified T Memory Stem Cells","volume":"7","author":"Biasco","year":"2015","journal-title":"Sci Transl Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66327","article-title":"Superior T Memory Stem Cell Persistence Supports Long-Lived T Cell Memory","volume":"123","author":"Lugli","year":"2013","journal-title":"J Clin Invest"},{"key":"B32","doi-asserted-by":"publisher","first-page":"282ra48","DOI":"10.1126\/scitranslmed.aaa3700","article-title":"Long-Lasting Stem Cell-Like Memory CD8(+) T Cells With a Naive-Like Profile Upon Yellow Fever Vaccination","volume":"7","author":"Fuertes Marraco","year":"2015","journal-title":"Sci Transl Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e23013","DOI":"10.7554\/eLife.23013","article-title":"Memory Cd4 T Cell Subsets are Kinetically Heterogeneous and Replenished From Naive T Cells at High Levels","volume":"6","author":"Gossel","year":"2017","journal-title":"Elife"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V87.2.423.bloodjournal872423","article-title":"Leukemia and Lymphoma in Ataxia Telangiectasia","volume":"87","author":"Taylor","year":"1996","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13578-020-0376-x","article-title":"ATM, ATR and DNA-PKcs Kinases-the Lessons From the Mouse Models: Inhibition\u2009\u2260\u2009Deletion","volume":"10","author":"Menolfi","year":"2020","journal-title":"Cell Bioscience"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0791-5","article-title":"Two Subsets of Stem-Like CD8(+)Memory T Cell Progenitors With Distinct Fate Commitments in Humans","volume":"21","author":"Galletti","year":"2020","journal-title":"Nat Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-016-0363-5","article-title":"Circulating T Cells of Patients With Nijmegen Breakage Syndrome Show Signs of Senescence","volume":"37","author":"Meijers","year":"2017","journal-title":"J Clin Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.686333\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T08:43:40Z","timestamp":1624524220000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.686333\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,24]]},"references-count":37,"alternative-id":["10.3389\/fimmu.2021.686333"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.686333","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,24]]},"article-number":"686333"}}