RT Journal Article
T1 Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions
A1 Briones Contreras, Alejandro
A1 Marín Marín, Ana Victoria
A1 Chaparro García, Rebeca
A1 López Nevado, Marta
A1 Abia, David
A1 Estevez Benito, Ivan
A1 Chacón Arguedas, Carlos Daniel
A1 Fernández Malavé, Edgar Gonzalo
A1 Cárdenas Mastrascusa, Paula Patricia
A1 Regueiro González-Barros, José Ramón
AB BackgroundThe 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.PurposeTo compare the capability of somatic revertant variants of CD247 germline changes (p.M1T and p.Q70X) to restore TCR expression and function.MethodsCD247 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.ResultsMA5.8 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.ConclusionSomatic 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.
PB Springer
YR 2025
FD 2025-07-25
LK https://hdl.handle.net/20.500.14352/124780
UL https://hdl.handle.net/20.500.14352/124780
LA eng
NO Briones, A.C., Marin, A.V., Chaparro-García, R. et al. Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions. J Clin Immunol 45, 116 (2025). https://doi.org/10.1007/s10875-025-01908-9
NO Ministerio de Economía y Competitividad (España)
NO Comunidad Autónoma de Madrid
NO Asociación Española Contra el Cáncer
DS Docta Complutense
RD 20 ene 2026