Analyses of thymocyte commitment to regulatory T cell lineage in thymus of healthy subjects and patients with 22q11.2 deletion syndrome

被引:0
作者
Borna, Simon [1 ]
Dejene, Beruh [1 ]
Lakshmanan, Uma [1 ]
Schulze, Janika [2 ]
Weinberg, Kenneth [1 ,3 ]
Bacchetta, Rosa [1 ,3 ]
机构
[1] Stanford Univ, Sch Med, Dept Pediat, Div Hematol Oncol Stem Cell Transplantat & Regener, Stanford, CA 94305 USA
[2] Epimune GmbH, Berlin, Germany
[3] Stanford Univ, Sch Med, Ctr Definit & Curat Med CDCM, Stanford, CA 94305 USA
来源
FRONTIERS IN IMMUNOLOGY | 2023年 / 14卷
关键词
Treg; regulatory T cell; 22q11; 2DS; TSDR; Treg progenitors; FOXP3; DEFICIENCY; AUTOIMMUNITY; HOMEOSTASIS; EXPRESSION;
D O I
10.3389/fimmu.2023.1088059
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The Chromosome 22q11.2 deletion syndrome (22q11.2DS) results in an inborn error of immunity due to defective thymic organogenesis. Immunological abnormalities in 22q11.2DS patients are thymic hypoplasia, reduced output of T lymphocytes by the thymus, immunodeficiency and increased incidence of autoimmunity. While the precise mechanism responsible for increased incidence of autoimmunity is not completely understood, a previous study suggested a defect in regulatory T cells (Treg) cell lineage commitment during T cell development in thymus. Here, we aimed to analyze this defect in more detail. Since Treg development in human is still ill-defined, we first analyzed where Treg lineage commitment occurs. We performed systematic epigenetic analyses of the Treg specific demethylation region (TSDR) of the FOXP3 gene in sorted thymocytes at different developmental stages. We defined CD3+CD4+CD8+ FOXP3+CD25+ as the T cell developmental stage in human where TSDR demethylation first occurs. Using this knowledge, we analyzed the intrathymic defect in Treg development in 22q11.2DS patients by combination of TSDR, CD3, CD4, CD8 locus epigenetics and multicolor flow cytometry. Our data showed no significant differences in Treg cell frequencies nor in their basic phenotype. Collectively, these data suggest that although 22q11.2DS patients present with reduced thymic size and T cell output, the frequencies and the phenotype of Treg cell at each developmental stage are surprisingly well preserved.
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页数:8
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共 27 条
  • [1] DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells
    Baron, Udo
    Floess, Stefan
    Wieczorek, Georg
    Baumann, Katrin
    Gruetzkau, Andreas
    Dong, Jun
    Thiel, Andreas
    Boeld, Tina J.
    Hoffmann, Petra
    Edinger, Matthias
    Tuerbachova, Ivana
    Hamann, Alf
    Olek, Sven
    Huehn, Jochen
    [J]. EUROPEAN JOURNAL OF IMMUNOLOGY, 2007, 37 (09) : 2378 - 2389
  • [2] Epigenetic immune cell counting in human blood samples for immunodiagnostics
    Baron, Udo
    Werner, Jeannette
    Schildknecht, Konstantin
    Schulze, Janika J.
    Mulu, Andargaschew
    Liebert, Uwe-Gerd
    Sack, Ulrich
    Speckmann, Carsten
    Gossen, Manfred
    Wong, Ronald J.
    Stevenson, David K.
    Babel, Nina
    Schuermann, Dirk
    Baldinger, Tina
    Bacchetta, Rosa
    Gruetzkau, Andreas
    Borte, Stephan
    Olek, Sven
    [J]. SCIENCE TRANSLATIONAL MEDICINE, 2018, 10 (452)
  • [3] Towards gene therapy for IPEX syndrome
    Borna, Simon
    Lee, Esmond
    Sato, Yohei
    Bacchetta, Rosa
    [J]. EUROPEAN JOURNAL OF IMMUNOLOGY, 2022, 52 (05) : 705 - 716
  • [4] Clinical Manifestations of 22q11.2 Deletion Syndrome
    Cirillo, Annapaola
    Lioncino, Michele
    Maratea, Annachiara
    Passariello, Annalisa
    Fusco, Adelaide
    Fratta, Fiorella
    Monda, Emanuele
    Caiazza, Martina
    Signore, Giovanni
    Esposito, Augusto
    Baban, Anwar
    Versacci, Paolo
    Putotto, Carolina
    Marino, Bruno
    Pignata, Claudio
    Cirillo, Emilia
    Giardino, Giuliana
    Sarubbi, Berardo
    Limongelli, Giuseppe
    Russo, Maria Giovanna
    [J]. HEART FAILURE CLINICS, 2022, 18 (01) : 155 - 164
  • [5] Davies K, 2001, J RHEUMATOL, V28, P2326
  • [6] DENNING SM, 1987, J IMMUNOL, V138, P680
  • [7] Autoimmunity and regulatory T cells in 22q11.2 deletion syndrome patients
    Di Cesare, Silvia
    Puliafito, Pamela
    Ariganello, Paola
    Marcovecchio, Genni Enza
    Mandolesi, Martina
    Capolino, Rossella
    Digilio, Maria Cristina
    Aiuti, Alessandro
    Rossi, Paolo
    Cancrini, Caterina
    [J]. PEDIATRIC ALLERGY AND IMMUNOLOGY, 2015, 26 (06) : 591 - 594
  • [8] The Genetics and Epigenetics of 22q11.2 Deletion Syndrome
    Du, Qiumei
    de la Morena, M. Teresa
    van Oers, Nicolai S. C.
    [J]. FRONTIERS IN GENETICS, 2020, 10
  • [9] Low Thymic Output, Peripheral Homeostasis Deregulation, and Hastened Regulatory T Cells Differentiation in Children with 22q11.2 Deletion Syndrome
    Ferrando-Martinez, Sara
    Lorente, Raquel
    Gurbindo, Dolores
    Isabel De Jose, Ma
    Leal, Manuel
    Angeles Munoz-Fernandez, Ma
    Correa-Rocha, Rafael
    [J]. JOURNAL OF PEDIATRICS, 2014, 164 (04) : 882 - 889
  • [10] Antibody deficiency and autoimmunity in 22q11.2 deletion syndrome
    Gennery, AR
    Barge, D
    O'Sullivan, JJ
    Flood, TJ
    Abinun, M
    Cant, AJ
    [J]. ARCHIVES OF DISEASE IN CHILDHOOD, 2002, 86 (06) : 422 - 425