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

Gil, J., Busto, E. M., Garcillán, B., Chean, C., Garcia-Rodriguez, M. C., Diaz-Alderete, A., et al. (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, 3872-3876.

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 Creators:
Gil, Juana, Author
Busto, Elena M., Author
Garcillán, Beatriz, Author
Chean, Carmen, Author
Garcia-Rodriguez, Maria Cruz, Author
Diaz-Alderete, Andrea, Author
Navarro, Joaquin, Author
Reiné, Jesús, Author
Mencia, Angeles, Author
Gurbindo, Dolores, Author
Beléndez, Cristina, Author
Gordillo, Isabel, Author
Duchniewicz, Marlena1, Author              
Höhne, Kerstin2, Author              
Garcia-Sánchez, Félix, Author
Fernández-Cruz, Eduardo, Author
López-Granados, Eduardo, Author
Schamel, Wolfgang W. A.2, Author              
Moreno-Pelayo, Miguel A., Author
Recio, Maria J., Author
Regueiro, José R., Author more..
Affiliations:
1Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243641              
2Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243645              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2011-10
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 576733
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Title: The Journal of Clinical Investigation
  Alternative Title : J. Clin. Invest.
Source Genre: Journal
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Pages: - Volume / Issue: 121 Sequence Number: - Start / End Page: 3872 - 3876 Identifier: -