CD3G or CD3D Knockdown in Mature, but Not Immature, T Lymphocytes Similarly Cripples the Human TCRαβ Complex

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dc.contributor.authorGarcillán Goyoaga, Beatriz de
dc.contributor.authorFuentes, Patricia
dc.contributor.authorMarín Marín, Ana Victoria
dc.contributor.authorFernández Megido, Rebeca
dc.contributor.authorChacón Arguedas, Carlos Daniel
dc.contributor.authorS. Mazariegos, Marina
dc.contributor.authorGonzález Laborda, Raquel
dc.contributor.authorJiménez Reinoso, Anaïs
dc.contributor.authorMuñoz Ruiz, Miguel
dc.contributor.authorCárdenas Mastracusa, Paula
dc.contributor.authorFernández-Malavé, Edgar
dc.contributor.authorToribio, Maria Luisa
dc.contributor.authorRegueiro González-Barros, José Ramón
dc.date.accessioned2023-06-17T09:17:47Z
dc.date.available2023-06-17T09:17:47Z
dc.date.issued2021-06-25
dc.description.abstractThe human αβ T-cell receptor (TCR) is composed of a variable heterodimer (TCRαβ) and three invariant dimers (CD3γε, CD3δε, and ζζ/CD2472). The role of each invariant chain in the stepwise interactions among TCR chains along the assembly is still not fully understood. Despite the high sequence homology between CD3γ and CD3δ, the clinical consequences of the corresponding immunodeficiencies (ID) in humans are very different (mild and severe, respectively), and mouse models do not recapitulate findings in human ID. To try to understand such disparities, we stably knocked down (KD) CD3D or CD3G expression in the human Jurkat T-cell line and analyzed comparatively their impact on TCRαβ assembly, transport, and surface expression. The results indicated that TCR ensembles were less stable and CD3ε levels were lower when CD3γ, rather than CD3δ, was scarce. However, both defective TCR ensembles were strongly retained in the ER, lacked ζζ/CD2472, and barely reached the T-cell surface (<11% of normal controls) in any of the CD3 KD cells. This is in sharp contrast to human CD3γ ID, whose mature T cells express higher levels of surface TCR (>30% vs. normal controls). CD3 KD of human T-cell progenitors followed by mouse fetal thymus organ cultures showed high plasticity in emerging immature polyclonal T lymphocytes that allowed for the expression of significant TCR levels which may then signal for survival in CD3γ, but not in CD3δ deficiency, and explain the immunological and clinical disparities of such ID cases.
dc.description.departmentDepto. de Inmunología, Oftalmología y ORL
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Economía y Competitividad (MINECO)
dc.description.sponsorshipComunidad de Madrid
dc.description.sponsorshipAsociación Española Contra el Cáncer (AECC)
dc.description.sponsorshipUniversidad Complutense de Madrid/Harvard University
dc.description.sponsorshipFundación Ramón Areces
dc.description.sponsorshipFundación Unoentrecienmil
dc.description.statuspub
dc.eprint.idhttps://eprints.ucm.es/id/eprint/68949
dc.identifier.doi10.3389/fcell.2021.608490
dc.identifier.issn2296-634X
dc.identifier.officialurlhttps://doi.org/10.3389/fcell.2021.608490
dc.identifier.relatedurlhttps://www.frontiersin.org/articles/10.3389/fcell.2021.608490/full
dc.identifier.urihttps://hdl.handle.net/20.500.14352/8553
dc.issue.number608490
dc.journal.titleFrontiers in Cell and Developmental Biology
dc.language.isoeng
dc.publisherFrontiers Media
dc.relation.projectIDRTI2018-095673-B-I00; PID2019-105623RB-I00; BES-2012-055054.
dc.relation.projectIDCAM B2017/BMD3673)
dc.relation.projectIDAECC PROYE20084REGU and CICPF18030TORI
dc.relation.projectIDCT46/15
dc.rightsAtribución 3.0 España
dc.rights.accessRightsopen access
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/es/
dc.subject.keywordCD3G
dc.subject.keywordCD3D
dc.subject.keywordshRNA knockdown
dc.subject.keywordT-cell receptor (TCR)
dc.subject.keywordTCR assembly
dc.subject.keywordT-cell progenitors
dc.subject.keywordimmunodeficiency
dc.subject.ucmMedicina
dc.subject.ucmOncología
dc.subject.unesco32 Ciencias Médicas
dc.subject.unesco3201.01 Oncología
dc.titleCD3G or CD3D Knockdown in Mature, but Not Immature, T Lymphocytes Similarly Cripples the Human TCRαβ Complex
dc.typejournal article
dc.volume.number9
dspace.entity.typePublication
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relation.isAuthorOfPublication.latestForDiscoveryf26d4a4d-989c-45c3-aea2-170d1bf0c1db
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