CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes

The mechanisms that control the inflammatory–immune response play a key role in tissue remodelling in cardiovascular diseases. T cell activation receptor CD69 binds to oxidized low-density lipoprotein (oxLDL), inducing the expression of anti-inflammatory NR4A nuclear receptors and modulating inflamm...

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Authors: Jiménez-Fernández, María, Rodríguez-Sinovas, Cristina, Cañes, Laia, Ballester-Servera, Carme, Vara, Alicia, Requena, Silvia, Fuente, Hortensia de la, Martínez-González, José, Sánchez-Madrid, Francisco
Format: article
Status:Published version
Publication Date:2022
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/288021
Online Access:http://hdl.handle.net/10261/288021
Access Level:Open access
Keyword:CD69 leucocyte activation receptor
oxLDL
Cardiovascular disease
Programmed Death 1 (PD-1)
Anti-inflammatory response
Inflamed aorta
id ES_8dc6c71efb938eee080b2488966e27bb
oai_identifier_str oai:digital.csic.es:10261/288021
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes
title CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes
spellingShingle CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes
Jiménez-Fernández, María
CD69 leucocyte activation receptor
oxLDL
Cardiovascular disease
Programmed Death 1 (PD-1)
Anti-inflammatory response
Inflamed aorta
title_short CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes
title_full CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes
title_fullStr CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes
title_full_unstemmed CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes
title_sort CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes
dc.creator.none.fl_str_mv Jiménez-Fernández, María
Rodríguez-Sinovas, Cristina
Cañes, Laia
Ballester-Servera, Carme
Vara, Alicia
Requena, Silvia
Fuente, Hortensia de la
Martínez-González, José
Sánchez-Madrid, Francisco
author Jiménez-Fernández, María
author_facet Jiménez-Fernández, María
Rodríguez-Sinovas, Cristina
Cañes, Laia
Ballester-Servera, Carme
Vara, Alicia
Requena, Silvia
Fuente, Hortensia de la
Martínez-González, José
Sánchez-Madrid, Francisco
author_role author
author2 Rodríguez-Sinovas, Cristina
Cañes, Laia
Ballester-Servera, Carme
Vara, Alicia
Requena, Silvia
Fuente, Hortensia de la
Martínez-González, José
Sánchez-Madrid, Francisco
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Conferencia de Rectores de las Universidades Españolas
Consejo Superior de Investigaciones Científicas (España)
Comunidad de Madrid
Fundación Ramón Areces
Fundación la Caixa
Agencia Estatal de Investigación (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Ministerio de Ciencia e Innovación (España)
Generalitat de Catalunya
Instituto de Salud Carlos III
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv CD69 leucocyte activation receptor
oxLDL
Cardiovascular disease
Programmed Death 1 (PD-1)
Anti-inflammatory response
Inflamed aorta
topic CD69 leucocyte activation receptor
oxLDL
Cardiovascular disease
Programmed Death 1 (PD-1)
Anti-inflammatory response
Inflamed aorta
description The mechanisms that control the inflammatory–immune response play a key role in tissue remodelling in cardiovascular diseases. T cell activation receptor CD69 binds to oxidized low-density lipoprotein (oxLDL), inducing the expression of anti-inflammatory NR4A nuclear receptors and modulating inflammation in atherosclerosis. To understand the downstream T cell responses triggered by the CD69-oxLDL binding, we incubated CD69-expressing Jurkat T cells with oxLDL. RNA sequencing revealed a differential gene expression profile dependent on the presence of CD69 and the degree of LDL oxidation. CD69-oxLDL binding induced the expression of NR4A receptors (NR4A1 and NR4A3), but also of PD-1. These results were confirmed using oxLDL and a monoclonal antibody against CD69 in CD69-expressing Jurkat and primary CD4 + lymphocytes. CD69-mediated induction of PD-1 and NR4A3 was dependent on NFAT activation. Silencing NR4A3 slightly increased PD-1 levels, suggesting a potential regulation of PD-1 by this receptor. Moreover, expression of PD-1, CD69 and NR4A3 was increased in human arteries with chronic inflammation compared to healthy controls, with a strong correlation between PD-1 and CD69 mRNA expression (r = 0.655 P < 0.0001). Moreover, PD-1 was expressed in areas enriched in CD3 infiltrating T cells. Our results underscore a novel mechanism of PD-1 induction independent of TCR signalling that might contribute to the role of CD69 in the modulation of inflammation and vascular remodelling in cardiovascular diseases.
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/288021
url http://hdl.handle.net/10261/288021
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
S2017/BMD-3671/INFLAMUNE-CM
info:eu-repo/grantAgreement/AEI//PDC2021-121719-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094727-B-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-120412RB-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at 10.1007/s00018-022-04481-1
http://dx.doi.org/10.1007/s00018-022-04481-1
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature
Birkhäuser Verlag
publisher.none.fl_str_mv Springer Nature
Birkhäuser Verlag
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
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spelling CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytesJiménez-Fernández, MaríaRodríguez-Sinovas, CristinaCañes, LaiaBallester-Servera, CarmeVara, AliciaRequena, SilviaFuente, Hortensia de laMartínez-González, JoséSánchez-Madrid, FranciscoCD69 leucocyte activation receptoroxLDLCardiovascular diseaseProgrammed Death 1 (PD-1)Anti-inflammatory responseInflamed aortaThe mechanisms that control the inflammatory–immune response play a key role in tissue remodelling in cardiovascular diseases. T cell activation receptor CD69 binds to oxidized low-density lipoprotein (oxLDL), inducing the expression of anti-inflammatory NR4A nuclear receptors and modulating inflammation in atherosclerosis. To understand the downstream T cell responses triggered by the CD69-oxLDL binding, we incubated CD69-expressing Jurkat T cells with oxLDL. RNA sequencing revealed a differential gene expression profile dependent on the presence of CD69 and the degree of LDL oxidation. CD69-oxLDL binding induced the expression of NR4A receptors (NR4A1 and NR4A3), but also of PD-1. These results were confirmed using oxLDL and a monoclonal antibody against CD69 in CD69-expressing Jurkat and primary CD4 + lymphocytes. CD69-mediated induction of PD-1 and NR4A3 was dependent on NFAT activation. Silencing NR4A3 slightly increased PD-1 levels, suggesting a potential regulation of PD-1 by this receptor. Moreover, expression of PD-1, CD69 and NR4A3 was increased in human arteries with chronic inflammation compared to healthy controls, with a strong correlation between PD-1 and CD69 mRNA expression (r = 0.655 P < 0.0001). Moreover, PD-1 was expressed in areas enriched in CD3 infiltrating T cells. Our results underscore a novel mechanism of PD-1 induction independent of TCR signalling that might contribute to the role of CD69 in the modulation of inflammation and vascular remodelling in cardiovascular diseases.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by grant S2017/BMD-3671-INFLAMUNE-CM from the Comunidad de Madrid, a grant from the Ramón Areces Foundation “Ciencias de la Vida y la Salud”, “La Caixa” Banking Foundation (HR17-00016) to FSM; grants PDC2021-121719-I00 and PDI-2020-120412RB-I00 to FSM, and RTI2018-094727-B-100 to JMG funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”; the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR-00333) to JMG; and a grant from the Instituto de Salud Carlos III (PI18/0919) to CR. M. Jiménez-Fernández is supported by a FPI-Severo Ochoa-CNIC (PRE2019-087941); C. Ballester-Servera is supported by a FPU fellowship (Ministerio de Universidades).Springer NatureBirkhäuser VerlagConferencia de Rectores de las Universidades EspañolasConsejo Superior de Investigaciones Científicas (España)Comunidad de MadridFundación Ramón ArecesFundación la CaixaAgencia Estatal de Investigación (España)Ministerio de Ciencia, Innovación y Universidades (España)Ministerio de Ciencia e Innovación (España)Generalitat de CatalunyaInstituto de Salud Carlos IIIEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2023202320222023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/288021reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#S2017/BMD-3671/INFLAMUNE-CMinfo:eu-repo/grantAgreement/AEI//PDC2021-121719-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-094727-B-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-120412RB-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at 10.1007/s00018-022-04481-1http://dx.doi.org/10.1007/s00018-022-04481-1Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2880212026-05-22T06:33:51Z
score 15.81155

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