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

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Garcillán Goyoaga, Beatriz de and Fuentes, Patricia and Marín Marín, Ana Victoria and Fernández Megido, Rebeca and Chacón Arguedas, Carlos Daniel and S. Mazariegos, Marina and González Laborda, Raquel and Jiménez Reinoso, Anaïs and Muñoz Ruiz, Miguel and Cárdenas Mastracusa, Paula and Fernández-Malavé, Edgar and Toribio, Maria Luisa and Regueiro González-Barros, José Ramón (2021) CD3G or CD3D Knockdown in Mature, but Not Immature, T Lymphocytes Similarly Cripples the Human TCRαβ Complex. Frontiers in Cell and Developmental Biology, 9 (608490). ISSN 2296-634X

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Official URL: https://doi.org/10.3389/fcell.2021.608490




Abstract

The 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.


Item Type:Article
Uncontrolled Keywords:CD3G, CD3D, shRNA knockdown, T-cell receptor (TCR), TCR assembly, T-cell progenitors, immunodeficiency
Subjects:Medical sciences > Medicine
Medical sciences > Medicine > Oncology
ID Code:68949
Deposited On:14 Dec 2021 11:55
Last Modified:14 Dec 2021 11:55

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