A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a Tαβ–Tγδ+B+NK+ human SCID
| Autor: | Wolfgang W. A. Schamel, Eduardo López-Granados, Joaquín Navarro, José R. Regueiro, Marlena Duchniewicz, Elena M. Busto, Andrea Diaz-Alderete, Kerstin Höhne, Maria Cruz García-Rodríguez, Beatriz Garcillán, Cristina Beléndez, Isabel Gordillo, Juana Gil, Maria J. Recio, Eduardo Fernández-Cruz, Carmen Chean, Ángeles Mencía, Félix García-Sánchez, M A Moreno-Pelayo, Jesús Reiné, Dolores Gurbindo |
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| Rok vydání: | 2011 |
| Předmět: |
Male
CD3 Complex Receptors Antigen T-Cell alpha-beta T cell DNA Mutational Analysis Cell Biology medicine.disease_cause Mice Antigen T-Lymphocyte Subsets medicine Animals Humans Cytotoxic T cell B cell B-Lymphocytes Severe combined immunodeficiency Mutation Base Sequence Brief Report T-cell receptor Infant Receptors Antigen T-Cell gamma-delta General Medicine medicine.disease Molecular biology Pedigree Killer Cells Natural medicine.anatomical_structure Female Severe Combined Immunodeficiency RNA Splice Sites |
| Zdroj: | Journal of Clinical Investigation. 121:3872-3876 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci44254 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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