A leaky mutation in CD3D differentially affects [alpha][Beta] and [gamma][delta] T cells and leads to a T[alpha][Beta]^sup -^T[gamma][delta]^sup +^B^sup +^NK^sup +^ human SCID

• Published in: The Journal of clinical investigation Vol. 121; no. 10; p. 3872
• Main Authors: Gil, Juana, Busto, Elena M, Garcillán, Beatriz, Chean, Carmen, García-Rodríguez, Maria Cruz, Díaz-Alderete, Andrea, Navarro, Joaquín, Reiné, Jesús, Mencía, Angeles, Gurbindo, Dolores, Beléndez, Cristina, Gordillo, Isabel, Duchniewicz, Marlena, Höhne, Kerstin, García-Sánchez, Félix, Fernández-Cruz, Eduardo, López-Granados, Eduardo, Schamel, Wolfgang W A, Moreno-Pelayo, Miguel A, Recio, María J, Regueiro, José R
• Format: Journal Article
• Language: English
• Published: Ann Arbor American Society for Clinical Investigation 01.10.2011
• Subjects: Biomedical research
• ISSN: 0021-9738; 1558-8238

T cells recognize antigens via their cell surface TCR and are classified as either α[beta] or γδ depending on the variable chains in their TCR, α and [beta] or γ and δ, respectively. Both α[beta] 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 α[beta] T cell-specific defect. Here, we report 2 unrelated cases of SCID with a selective block in α[beta] 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 α[beta] 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 α[beta] T cells, surface TCR expression was more reduced in γδ than in α[beta] T cells. Analysis of individuals with this CD3D mutation thus demonstrates the contrasting CD3δ requirements for α[beta] 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.