Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity

Autores
Araya, Paula; Waugh, Katherine A.; Sullivan, Kelly D.; Núñez, Nicolás; Roselli, Emiliano; Smith, Keith P.; Granrath, Ross E.; Rachubinski, Angela L.; Enriquez Estrada, Belinda; Butcher, Eric T.; Minter, Ross; Tuttle, Kathryn D.; Bruno, Tullia C.; Maccioni, Mariana; Espinosa, Joaquín M.
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A–D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.
Fil: Araya, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Waugh, Katherine A.. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Sullivan, Kelly D.. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Núñez, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Roselli, Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Smith, Keith P.. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Granrath, Ross E.. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Rachubinski, Angela L.. University of Colorado; Estados Unidos
Fil: Enriquez Estrada, Belinda. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Butcher, Eric T.. University of Colorado; Estados Unidos
Fil: Minter, Ross. University of Colorado; Estados Unidos
Fil: Tuttle, Kathryn D.. University of Colorado; Estados Unidos
Fil: Bruno, Tullia C.. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Maccioni, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Espinosa, Joaquín M.. University Of Colorado. School Of Medicine.; Estados Unidos
Materia
AUTOIMMUNITY
INFLAMMATION
T CELLS
TRISOMY 21
TYPE I INTERFERON
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/138092
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/138092
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivityAraya, PaulaWaugh, Katherine A.Sullivan, Kelly D.Núñez, NicolásRoselli, EmilianoSmith, Keith P.Granrath, Ross E.Rachubinski, Angela L.Enriquez Estrada, BelindaButcher, Eric T.Minter, RossTuttle, Kathryn D.Bruno, Tullia C.Maccioni, MarianaEspinosa, Joaquín M.AUTOIMMUNITYINFLAMMATIONT CELLSTRISOMY 21TYPE I INTERFERONhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A–D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.Fil: Araya, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Waugh, Katherine A.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Sullivan, Kelly D.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Núñez, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Roselli, Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Smith, Keith P.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Granrath, Ross E.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Rachubinski, Angela L.. University of Colorado; Estados UnidosFil: Enriquez Estrada, Belinda. University Of Colorado. School Of Medicine.; Estados UnidosFil: Butcher, Eric T.. University of Colorado; Estados UnidosFil: Minter, Ross. University of Colorado; Estados UnidosFil: Tuttle, Kathryn D.. University of Colorado; Estados UnidosFil: Bruno, Tullia C.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Maccioni, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Espinosa, Joaquín M.. University Of Colorado. School Of Medicine.; Estados UnidosNational Academy of Sciences2019-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/pdfhttp://hdl.handle.net/11336/138092Araya, Paula; Waugh, Katherine A.; Sullivan, Kelly D.; Núñez, Nicolás; Roselli, Emiliano; et al.; Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 11-20190027-8424CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/lookup/doi/10.1073/pnas.1908129116info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1908129116info:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/content/116/48/24231info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:11:29Zoai:ri.conicet.gov.ar:11336/138092instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:11:29.477CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity
title Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity
spellingShingle Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity
Araya, Paula
AUTOIMMUNITY
INFLAMMATION
T CELLS
TRISOMY 21
TYPE I INTERFERON
title_short Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity
title_full Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity
title_fullStr Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity
title_full_unstemmed Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity
title_sort Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity
dc.creator.none.fl_str_mv Araya, Paula
Waugh, Katherine A.
Sullivan, Kelly D.
Núñez, Nicolás
Roselli, Emiliano
Smith, Keith P.
Granrath, Ross E.
Rachubinski, Angela L.
Enriquez Estrada, Belinda
Butcher, Eric T.
Minter, Ross
Tuttle, Kathryn D.
Bruno, Tullia C.
Maccioni, Mariana
Espinosa, Joaquín M.
author Araya, Paula
author_facet Araya, Paula
Waugh, Katherine A.
Sullivan, Kelly D.
Núñez, Nicolás
Roselli, Emiliano
Smith, Keith P.
Granrath, Ross E.
Rachubinski, Angela L.
Enriquez Estrada, Belinda
Butcher, Eric T.
Minter, Ross
Tuttle, Kathryn D.
Bruno, Tullia C.
Maccioni, Mariana
Espinosa, Joaquín M.
author_role author
author2 Waugh, Katherine A.
Sullivan, Kelly D.
Núñez, Nicolás
Roselli, Emiliano
Smith, Keith P.
Granrath, Ross E.
Rachubinski, Angela L.
Enriquez Estrada, Belinda
Butcher, Eric T.
Minter, Ross
Tuttle, Kathryn D.
Bruno, Tullia C.
Maccioni, Mariana
Espinosa, Joaquín M.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv AUTOIMMUNITY
INFLAMMATION
T CELLS
TRISOMY 21
TYPE I INTERFERON
topic AUTOIMMUNITY
INFLAMMATION
T CELLS
TRISOMY 21
TYPE I INTERFERON
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A–D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.
Fil: Araya, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Waugh, Katherine A.. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Sullivan, Kelly D.. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Núñez, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Roselli, Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Smith, Keith P.. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Granrath, Ross E.. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Rachubinski, Angela L.. University of Colorado; Estados Unidos
Fil: Enriquez Estrada, Belinda. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Butcher, Eric T.. University of Colorado; Estados Unidos
Fil: Minter, Ross. University of Colorado; Estados Unidos
Fil: Tuttle, Kathryn D.. University of Colorado; Estados Unidos
Fil: Bruno, Tullia C.. University Of Colorado. School Of Medicine.; Estados Unidos
Fil: Maccioni, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Espinosa, Joaquín M.. University Of Colorado. School Of Medicine.; Estados Unidos
description Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A–D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.
publishDate 2019
dc.date.none.fl_str_mv 2019-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/138092
Araya, Paula; Waugh, Katherine A.; Sullivan, Kelly D.; Núñez, Nicolás; Roselli, Emiliano; et al.; Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 11-2019
0027-8424
CONICET Digital
CONICET
url http://hdl.handle.net/11336/138092
identifier_str_mv Araya, Paula; Waugh, Katherine A.; Sullivan, Kelly D.; Núñez, Nicolás; Roselli, Emiliano; et al.; Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 11-2019
0027-8424
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1908129116
info:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/content/116/48/24231
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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