RT Journal Article
T1 A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a Tαβ−Tγδ+B+NK+ human SCID
A1 Gil Calle, Juana Nelly
A1 Busto, Elena M
A1 Garcillán Goyoaga, Beatriz de
A1 Chean, Carmen
A1 García Rodríguez, María Cruz
A1 Díaz Alderete, Andrea
A1 Navarro, Joaquín
A1 Reiné Gutiérrez, Jesús
A1 Mencía, Ángeles
A1 Gurbindo, Dolores
A1 Beléndez, Cristina
A1 Gordillo, Isabel
A1 Duchniewicz, Marlena
A1 Höhne, Kerstin
A1 García Sánchez, Félix
A1 Fernández Cruz, Eduardo
A1 López Granados, Eduardo
A1 Schamel, Wolfgang W.A.
A1 Moreno Pelayo, Miguel A
A1 Recio Hoyas, María José
A1 Regueiro González-Barros, José Ramón
AB 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.
PB American Society for Clinical Investigation
SN 0021-9738; 1558-8238
YR 2011
FD 2011-10
LK https://hdl.handle.net/20.500.14352/43344
UL https://hdl.handle.net/20.500.14352/43344
LA eng
NO Ministerio de Ciencia e Innovación (MICINN)
NO Instituto de Salud Carlos III (ISCIII)
NO Deutsche-Forschungsgemeinschaft
NO Fundación Mutua Madrileña
DS Docta Complutense
RD 6 abr 2025