CD3G or CD3D Knockdown in Mature, but Not Immature, T Lymphocytes Similarly Cripples the Human TCRαβ Complex
| Autor: | Ana V. Marin, Daniel Chacon-Arguedas, Anaïs Jiménez-Reinoso, Miguel Muñoz-Ruiz, Raquel G. Laborda, Paula P. Cárdenas, Edgar Fernández-Malavé, Marina S. Mazariegos, Patricia Fuentes, Rebeca F. Megino, María L. Toribio, Beatriz Garcillán, José R. Regueiro |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Comunidad de Madrid, Asociación Española Contra el Cáncer, Fundación Ramón Areces, Fundación Unoentrecienmil |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
QH301-705.5 Medicina CD3 Jurkat cells Oncología Small hairpin RNA Cell and Developmental Biology 03 medical and health sciences 0302 clinical medicine Immunodeficiency shRNA knockdown Biology (General) Progenitor cell Receptor Original Research Gene knockdown biology TCR assembly T-cell receptor T-cell receptor (TCR) CD3D Cell Biology T-cell progenitors CD3G Cell biology 030104 developmental biology Polyclonal antibodies 030220 oncology & carcinogenesis biology.protein Developmental Biology |
| Zdroj: | E-Prints Complutense. Archivo Institucional de la UCM instname Digital.CSIC. Repositorio Institucional del CSIC Frontiers in Cell and Developmental Biology, Vol 9 (2021) Frontiers in Cell and Developmental Biology |
| ISSN: | 2296-634X |
| Popis: | The human αβ T-cell receptor (TCR) is composed of a variable heterodimer (TCRαβ) and three invariant dimers (CD3γε, CD3δε, and ζζ/CD247). 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/CD247, and barely reached the T-cell surface (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. Ministerio de Economía y Competitividad (MINECO RTI2018-095673-B-I00 and PID2019-105623RB-I00), Comunidad Autónoma deMadrid (CAM B2017/BMD3673), and Asociación Española Contra el Cáncer (AECC PROYE20084REGU and CICPF18030TORI), Fundación Ramón Areces, and Fundación Unoentrecienmil. AM was supported by Complutense/Harvard University scholarship CT46/15 and AJ-R by MINECO scholarship BES-2012-055054 |
| Databáze: | OpenAIRE |
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