RT Journal Article
T1 CD3G or CD3D Knockdown in Mature, but Not Immature, T Lymphocytes Similarly Cripples the Human TCRαβ Complex
A1 Garcillán Goyoaga, Beatriz de
A1 Fuentes, Patricia
A1 Marín Marín, Ana Victoria
A1 Fernández Megido, Rebeca
A1 Chacón Arguedas, Carlos Daniel
A1 S. Mazariegos, Marina
A1 González Laborda, Raquel
A1 Jiménez Reinoso, Anaïs
A1 Muñoz Ruiz, Miguel
A1 Cárdenas Mastracusa, Paula
A1 Fernández-Malavé, Edgar
A1 Toribio, Maria Luisa
A1 Regueiro González-Barros, José Ramón
AB 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.
PB Frontiers Media
SN 2296-634X
YR 2021
FD 2021-06-25
LK https://hdl.handle.net/20.500.14352/8553
UL https://hdl.handle.net/20.500.14352/8553
LA eng
NO Ministerio de Economía y Competitividad (MINECO)
NO Comunidad de Madrid
NO Asociación Española Contra el Cáncer (AECC)
NO Universidad Complutense de Madrid/Harvard University
NO Fundación Ramón Areces
NO Fundación Unoentrecienmil
DS Docta Complutense
RD 20 jul 2024