Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions

Background: The CD247 chain of the T-cell receptor (TCR) is essential for normal T cell development and function. Reported CD247-deficient patients showed severe immunodeficiency despite the presence of two populations of peripheral T cells, most with low TCR levels carrying the germline variant and...

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Autores: Briones, Alejandro C., Marin, Ana V., Chaparro-García, Rebeca, López-Nevado, Marta, Abia, David, Estevez-Benito, Ivan, Chacón-Arguedas, Daniel, Fernández-Malavé, Edgar, Cardenas, Paula P., Regueiro, José R.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/409976
Acceso en línea:http://hdl.handle.net/10261/409976
Access Level:acceso abierto
Palabra clave:CD247
CD3Z
TCR
Immunodeficiency
Somatic reversions
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spelling Discordant Restoration of TCR Expression and Function by CD247 Somatic ReversionsBriones, Alejandro C.Marin, Ana V.Chaparro-García, RebecaLópez-Nevado, MartaAbia, DavidEstevez-Benito, IvanChacón-Arguedas, DanielFernández-Malavé, EdgarCardenas, Paula P.Regueiro, José R.CD247CD3ZTCRImmunodeficiencySomatic reversionsBackground: The CD247 chain of the T-cell receptor (TCR) is essential for normal T cell development and function. Reported CD247-deficient patients showed severe immunodeficiency despite the presence of two populations of peripheral T cells, most with low TCR levels carrying the germline variant and a few with higher TCR levels due to somatic reversion. However, the revertant T cells remained a minority and did not improve the patients’ clinical status. Purpose: To compare the capability of somatic revertant variants of CD247 germline changes (p.M1T and p.Q70X) to restore TCR expression and function. Methods: CD247 wild-type (WT) and p.Q70L/W/Y somatic variants were individually introduced in CD247-deficient mouse (MA5.8), human mutant (PM1T), and CRISPR/Cas9-generated Jurkat (ZKO) T cell lines by nucleofection or transduction. Results: MA5.8 mouse T cells do not accurately model human CD247 deficiencies, as Q70X restores TCR expression in MA5.8 but not in human cells. In human cell models, all somatic revertant variants restored TCR expression with varying degrees (WT = Q70L > Q70W > Q70Y). In contrast, TCR-induced activation events, such as CD69/CD25 upregulation, showed a different hierarchy (WT = Q70W > Q70L = Q70Y). Furthermore, all CD247 somatic variants failed to induce TCR-mediated ZAP70 tyrosine phosphorylation compared to WT. Conclusion: Somatic reversions, such as those detected in patients with pathogenic CD247 germinal changes, display a discordant capability to rescue TCR expression versus function. These findings shed light on the role of CD247 in TCR expression and function during human T cell development, with implications for immunodeficiencies, as well as for the biological consequences of CD247 somatic mosaicism.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This study was supported by grants from the Ministerio de Economía y Competitividad (MINECO RED2022-134750-T, PID2021-125501OB-I00, and PID2024-155827OB-I00), the Comunidad Autónoma de Madrid (P2022/BMD-7278, PR38/21–13 ANTICIPA-CM and CAM B2017/BMD3673), and the Asociación Española Contra el Cáncer (AECC PROYE20084REGU). A.C.B. was supported by Complutense University scholarship Q16 (CT27/16 and CT31/21). P.P.C. was supported by the MINECO Juan de la Cierva—Incorporación fellowship (IJCI-2014–19262).Kluwer Academic/Plenum PublishersMinisterio de Economía y Competitividad (España)Comunidad de MadridAsociación Española Contra el CáncerUniversidad Complutense de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2025202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/409976reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-125501OB-I00http://dx.doi.org/10.1007/s10875-025-01908-9Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4099762026-05-22T06:33:51Z
dc.title.none.fl_str_mv Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions
title Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions
spellingShingle Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions
Briones, Alejandro C.
CD247
CD3Z
TCR
Immunodeficiency
Somatic reversions
title_short Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions
title_full Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions
title_fullStr Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions
title_full_unstemmed Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions
title_sort Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions
dc.creator.none.fl_str_mv Briones, Alejandro C.
Marin, Ana V.
Chaparro-García, Rebeca
López-Nevado, Marta
Abia, David
Estevez-Benito, Ivan
Chacón-Arguedas, Daniel
Fernández-Malavé, Edgar
Cardenas, Paula P.
Regueiro, José R.
author Briones, Alejandro C.
author_facet Briones, Alejandro C.
Marin, Ana V.
Chaparro-García, Rebeca
López-Nevado, Marta
Abia, David
Estevez-Benito, Ivan
Chacón-Arguedas, Daniel
Fernández-Malavé, Edgar
Cardenas, Paula P.
Regueiro, José R.
author_role author
author2 Marin, Ana V.
Chaparro-García, Rebeca
López-Nevado, Marta
Abia, David
Estevez-Benito, Ivan
Chacón-Arguedas, Daniel
Fernández-Malavé, Edgar
Cardenas, Paula P.
Regueiro, José R.
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Comunidad de Madrid
Asociación Española Contra el Cáncer
Universidad Complutense de Madrid
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv CD247
CD3Z
TCR
Immunodeficiency
Somatic reversions
topic CD247
CD3Z
TCR
Immunodeficiency
Somatic reversions
description Background: The CD247 chain of the T-cell receptor (TCR) is essential for normal T cell development and function. Reported CD247-deficient patients showed severe immunodeficiency despite the presence of two populations of peripheral T cells, most with low TCR levels carrying the germline variant and a few with higher TCR levels due to somatic reversion. However, the revertant T cells remained a minority and did not improve the patients’ clinical status. Purpose: To compare the capability of somatic revertant variants of CD247 germline changes (p.M1T and p.Q70X) to restore TCR expression and function. Methods: CD247 wild-type (WT) and p.Q70L/W/Y somatic variants were individually introduced in CD247-deficient mouse (MA5.8), human mutant (PM1T), and CRISPR/Cas9-generated Jurkat (ZKO) T cell lines by nucleofection or transduction. Results: MA5.8 mouse T cells do not accurately model human CD247 deficiencies, as Q70X restores TCR expression in MA5.8 but not in human cells. In human cell models, all somatic revertant variants restored TCR expression with varying degrees (WT = Q70L > Q70W > Q70Y). In contrast, TCR-induced activation events, such as CD69/CD25 upregulation, showed a different hierarchy (WT = Q70W > Q70L = Q70Y). Furthermore, all CD247 somatic variants failed to induce TCR-mediated ZAP70 tyrosine phosphorylation compared to WT. Conclusion: Somatic reversions, such as those detected in patients with pathogenic CD247 germinal changes, display a discordant capability to rescue TCR expression versus function. These findings shed light on the role of CD247 in TCR expression and function during human T cell development, with implications for immunodeficiencies, as well as for the biological consequences of CD247 somatic mosaicism.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
2025
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/10261/409976
url http://hdl.handle.net/10261/409976
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2021-125501OB-I00
http://dx.doi.org/10.1007/s10875-025-01908-9
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Kluwer Academic/Plenum Publishers
publisher.none.fl_str_mv Kluwer Academic/Plenum Publishers
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
repository.mail.fl_str_mv
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