A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a Tαβ−Tγδ+B+NK+ human SCID



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Gil Calle, Juana Nelly and Busto, Elena M and Garcillán Goyoaga, Beatriz de and Chean, Carmen and García Rodríguez, María Cruz and Díaz Alderete, Andrea and Navarro, Joaquín and Reiné Gutiérrez, Jesús and Mencía, Ángeles and Gurbindo, Dolores and Beléndez, Cristina and Gordillo, Isabel and Duchniewicz, Marlena and Höhne, Kerstin and García Sánchez, Félix and Fernández Cruz, Eduardo and López Granados, Eduardo and Schamel, Wolfgang W.A. and Moreno Pelayo, Miguel A and Recio Hoyas, María José and Regueiro González-Barros, José Ramón (2011) A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a Tαβ−Tγδ+B+NK+ human SCID. The Journal of Clinical Investigation, 121 (10). pp. 3872-3876. ISSN 0021-9738; 1558-8238

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Official URL: https://doi.org/10.1172/JCI44254


T cells recognize antigens via their cell surface TCR and are classified as either αβ or γδ depending on the variable chains in their TCR, α and β or γ and δ, respectively. Both αβ and γδ TCRs also contain several invariant chains, including CD3δ, which support surface TCR expression and transduce the TCR signal. Mutations in variable chains would be expected to affect a single T cell lineage, while mutations in the invariant chains would affect all T cells. Consistent with this, all CD3δ-deficient patients described to date showed a complete block in T cell development. However, CD3δ-KO mice have an αβ T cell–specific defect. Here, we report 2 unrelated cases of SCID with a selective block in αβ but not in γδ T cell development, associated with a new splicing mutation in the CD3D gene. The patients’ T cells showed reduced CD3D transcripts, CD3δ proteins, surface TCR, and early TCR signaling. Their lymph nodes showed severe T cell depletion, recent thymus emigrants in peripheral blood were strongly decreased, and the scant αβ T cells were oligoclonal. T cell–dependent B cell functions were also impaired, despite the presence of normal B cell numbers. Strikingly, despite the specific loss of αβ T cells, surface TCR expression was more reduced in γδ than in αβ T cells. Analysis of individuals with this CD3D mutation thus demonstrates the contrasting CD3δ requirements for αβ versus γδ T cell development and TCR expression in humans and highlights the diagnostic and clinical relevance of studying both TCR isotypes when a T cell defect is suspected.

Item Type:Article
Subjects:Medical sciences > Medicine > Immunology
ID Code:69226
Deposited On:16 Dec 2021 08:09
Last Modified:16 Dec 2021 09:56

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