Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development

Genni Enza Marcovecchio, Ileana Bortolomai, Francesca Ferrua, Elena Fontana, Luisa Imberti, Erika Conforti, Donato Amodio, Sonia Bergante, Giulia Macchiarulo, Veronica D'Oria, Francesca Conti, Silvia Di Cesare, Georgia Fousteri, Adriano Carotti, Alessandro Giamberti, Pietro Luigi Poliani, Luigi D Notarangelo, Caterina Cancrini, Anna Villa, Marita Bosticardo

Research output: Contribution to journalArticle

Abstract

The thymus plays a fundamental role in establishing and maintaining central and peripheral tolerance and defects in thymic architecture or AIRE expression result in the development of autoreactive lymphocytes. Patients with partial DiGeorge Syndrome (pDGS) and Down Syndrome (DS) present alterations in size and architecture of the thymus and higher risk to develop autoimmunity. We sought to evaluate thymic architecture and thymocyte development in DGS and DS patients and to determine the extent to which thymic defects result in immune dysregulation and T cell homeostasis perturbation in these patients. Thymi from pediatric patients and age-matched controls were obtained to evaluate cortex and medullary compartments, AIRE expression and thymocyte development. In the same patients we also characterized immunophenotype of peripheral T cells. Phenotypic and functional characterization of thymic and peripheral regulatory T (Treg) cells was finally assessed. Histologic analysis revealed peculiar alterations in thymic medulla size and maturation in DGS and DS patients. Perturbed distribution of thymocytes and altered thymic output was also observed. DGS patients showed lower mature CD4+ and CD8+ T cell frequency, associated with reduced proportion and function of Tregs both in thymus and peripheral blood. DS patients showed increased frequency of single positive (SP) thymocytes and thymic Treg cells. However, Tregs isolated both from thymus and peripheral blood of DS patients showed reduced suppressive ability. Our results provide novel insights on thymic defects associated with DGS and DS and their impact on peripheral immune dysregulation. Indeed, thymic abnormalities and defect in thymocyte development, in particular in Treg cell number and function could contribute in the pathogenesis of the immunodysregulation present in pDGS and in DS patients.

Original languageEnglish
Pages (from-to)447
JournalFrontiers in Immunology
Volume10
DOIs
Publication statusPublished - 2019

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DiGeorge Syndrome
Down Syndrome
Epithelium
T-Lymphocytes
Thymocytes
Thymus Gland
Regulatory T-Lymphocytes
Central Tolerance
Peripheral Tolerance
Autoimmunity
Homeostasis
Cell Count
Lymphocytes
Pediatrics

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Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development. / Marcovecchio, Genni Enza; Bortolomai, Ileana; Ferrua, Francesca; Fontana, Elena; Imberti, Luisa; Conforti, Erika; Amodio, Donato; Bergante, Sonia; Macchiarulo, Giulia; D'Oria, Veronica; Conti, Francesca; Di Cesare, Silvia; Fousteri, Georgia; Carotti, Adriano; Giamberti, Alessandro; Poliani, Pietro Luigi; Notarangelo, Luigi D; Cancrini, Caterina; Villa, Anna; Bosticardo, Marita.

In: Frontiers in Immunology, Vol. 10, 2019, p. 447.

Research output: Contribution to journalArticle

Marcovecchio, Genni Enza ; Bortolomai, Ileana ; Ferrua, Francesca ; Fontana, Elena ; Imberti, Luisa ; Conforti, Erika ; Amodio, Donato ; Bergante, Sonia ; Macchiarulo, Giulia ; D'Oria, Veronica ; Conti, Francesca ; Di Cesare, Silvia ; Fousteri, Georgia ; Carotti, Adriano ; Giamberti, Alessandro ; Poliani, Pietro Luigi ; Notarangelo, Luigi D ; Cancrini, Caterina ; Villa, Anna ; Bosticardo, Marita. / Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development. In: Frontiers in Immunology. 2019 ; Vol. 10. pp. 447.
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abstract = "The thymus plays a fundamental role in establishing and maintaining central and peripheral tolerance and defects in thymic architecture or AIRE expression result in the development of autoreactive lymphocytes. Patients with partial DiGeorge Syndrome (pDGS) and Down Syndrome (DS) present alterations in size and architecture of the thymus and higher risk to develop autoimmunity. We sought to evaluate thymic architecture and thymocyte development in DGS and DS patients and to determine the extent to which thymic defects result in immune dysregulation and T cell homeostasis perturbation in these patients. Thymi from pediatric patients and age-matched controls were obtained to evaluate cortex and medullary compartments, AIRE expression and thymocyte development. In the same patients we also characterized immunophenotype of peripheral T cells. Phenotypic and functional characterization of thymic and peripheral regulatory T (Treg) cells was finally assessed. Histologic analysis revealed peculiar alterations in thymic medulla size and maturation in DGS and DS patients. Perturbed distribution of thymocytes and altered thymic output was also observed. DGS patients showed lower mature CD4+ and CD8+ T cell frequency, associated with reduced proportion and function of Tregs both in thymus and peripheral blood. DS patients showed increased frequency of single positive (SP) thymocytes and thymic Treg cells. However, Tregs isolated both from thymus and peripheral blood of DS patients showed reduced suppressive ability. Our results provide novel insights on thymic defects associated with DGS and DS and their impact on peripheral immune dysregulation. Indeed, thymic abnormalities and defect in thymocyte development, in particular in Treg cell number and function could contribute in the pathogenesis of the immunodysregulation present in pDGS and in DS patients.",
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T1 - Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development

AU - Marcovecchio, Genni Enza

AU - Bortolomai, Ileana

AU - Ferrua, Francesca

AU - Fontana, Elena

AU - Imberti, Luisa

AU - Conforti, Erika

AU - Amodio, Donato

AU - Bergante, Sonia

AU - Macchiarulo, Giulia

AU - D'Oria, Veronica

AU - Conti, Francesca

AU - Di Cesare, Silvia

AU - Fousteri, Georgia

AU - Carotti, Adriano

AU - Giamberti, Alessandro

AU - Poliani, Pietro Luigi

AU - Notarangelo, Luigi D

AU - Cancrini, Caterina

AU - Villa, Anna

AU - Bosticardo, Marita

PY - 2019

Y1 - 2019

N2 - The thymus plays a fundamental role in establishing and maintaining central and peripheral tolerance and defects in thymic architecture or AIRE expression result in the development of autoreactive lymphocytes. Patients with partial DiGeorge Syndrome (pDGS) and Down Syndrome (DS) present alterations in size and architecture of the thymus and higher risk to develop autoimmunity. We sought to evaluate thymic architecture and thymocyte development in DGS and DS patients and to determine the extent to which thymic defects result in immune dysregulation and T cell homeostasis perturbation in these patients. Thymi from pediatric patients and age-matched controls were obtained to evaluate cortex and medullary compartments, AIRE expression and thymocyte development. In the same patients we also characterized immunophenotype of peripheral T cells. Phenotypic and functional characterization of thymic and peripheral regulatory T (Treg) cells was finally assessed. Histologic analysis revealed peculiar alterations in thymic medulla size and maturation in DGS and DS patients. Perturbed distribution of thymocytes and altered thymic output was also observed. DGS patients showed lower mature CD4+ and CD8+ T cell frequency, associated with reduced proportion and function of Tregs both in thymus and peripheral blood. DS patients showed increased frequency of single positive (SP) thymocytes and thymic Treg cells. However, Tregs isolated both from thymus and peripheral blood of DS patients showed reduced suppressive ability. Our results provide novel insights on thymic defects associated with DGS and DS and their impact on peripheral immune dysregulation. Indeed, thymic abnormalities and defect in thymocyte development, in particular in Treg cell number and function could contribute in the pathogenesis of the immunodysregulation present in pDGS and in DS patients.

AB - The thymus plays a fundamental role in establishing and maintaining central and peripheral tolerance and defects in thymic architecture or AIRE expression result in the development of autoreactive lymphocytes. Patients with partial DiGeorge Syndrome (pDGS) and Down Syndrome (DS) present alterations in size and architecture of the thymus and higher risk to develop autoimmunity. We sought to evaluate thymic architecture and thymocyte development in DGS and DS patients and to determine the extent to which thymic defects result in immune dysregulation and T cell homeostasis perturbation in these patients. Thymi from pediatric patients and age-matched controls were obtained to evaluate cortex and medullary compartments, AIRE expression and thymocyte development. In the same patients we also characterized immunophenotype of peripheral T cells. Phenotypic and functional characterization of thymic and peripheral regulatory T (Treg) cells was finally assessed. Histologic analysis revealed peculiar alterations in thymic medulla size and maturation in DGS and DS patients. Perturbed distribution of thymocytes and altered thymic output was also observed. DGS patients showed lower mature CD4+ and CD8+ T cell frequency, associated with reduced proportion and function of Tregs both in thymus and peripheral blood. DS patients showed increased frequency of single positive (SP) thymocytes and thymic Treg cells. However, Tregs isolated both from thymus and peripheral blood of DS patients showed reduced suppressive ability. Our results provide novel insights on thymic defects associated with DGS and DS and their impact on peripheral immune dysregulation. Indeed, thymic abnormalities and defect in thymocyte development, in particular in Treg cell number and function could contribute in the pathogenesis of the immunodysregulation present in pDGS and in DS patients.

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DO - 10.3389/fimmu.2019.00447

M3 - Article

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SP - 447

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

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