2026-06-27T15:46:46Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/1247802025-10-10T23:57:55Zcom_20.500.14352_14col_20.500.14352_15

Briones Contreras, Alejandro Marín Marín, Ana Victoria Chaparro García, Rebeca López Nevado, Marta Abia, David Estevez Benito, Ivan Chacón Arguedas, Carlos Daniel Fernández Malavé, Edgar Gonzalo Cárdenas Mastrascusa, Paula Patricia Regueiro González-Barros, José Ramón 2025-10-10T07:49:32Z 2025-10-10T07:49:32Z 2025-07-25 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 10.1007/s10875-025-01908-9 https://hdl.handle.net/20.500.14352/124780 1573-2592 https://doi.org/10.1007/s10875-025-01908-9 https://link.springer.com/article/10.1007/s10875-025-01908-9 Background The 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. Purpose To compare the capability of somatic revertant variants of CD247 germline changes (p.M1T and p.Q70X) to restore TCR expression and function. Methods CD247 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. Results MA5.8 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. Conclusion Somatic 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. eng http://creativecommons.org/licenses/by/4.0/ open access Attribution 4.0 International Discordant Restoration of TCR Expression and Function by CD247 Somatic Reversions journal article