title: A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a Tαβ-Tγδ+B+NK+ human SCID.
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.
authors.affiliation: Gregorio Maranon University Hospital, Madrid, Spain.
authors.forename: Juana
authors.initials: J
authors.lastname: Gil
authors.forename: Elena M
authors.initials: EM
authors.lastname: Busto
authors.forename: Beatriz
authors.initials: B
authors.lastname: Garcillán
authors.forename: Carmen
authors.initials: C
authors.lastname: Chean
authors.forename: Maria Cruz
authors.initials: MC
authors.lastname: García-Rodríguez
authors.forename: Andrea
authors.initials: A
authors.lastname: Díaz-Alderete
authors.forename: Joaquín
authors.initials: J
authors.lastname: Navarro
authors.forename: Jesús
authors.initials: J
authors.lastname: Reiné
authors.forename: Angeles
authors.initials: A
authors.lastname: Mencía
authors.forename: Dolores
authors.initials: D
authors.lastname: Gurbindo
authors.forename: Cristina
authors.initials: C
authors.lastname: Beléndez
authors.forename: Isabel
authors.initials: I
authors.lastname: Gordillo
authors.forename: Marlena
authors.initials: M
authors.lastname: Duchniewicz
authors.forename: Kerstin
authors.initials: K
authors.lastname: Höhne
authors.forename: Félix
authors.initials: F
authors.lastname: García-Sánchez
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernández-Cruz
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Granados
authors.forename: Wolfgang W A
authors.initials: WW
authors.lastname: Schamel
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Moreno-Pelayo
authors.forename: María J
authors.initials: MJ
authors.lastname: Recio
authors.forename: José R
authors.initials: JR
authors.lastname: Regueiro
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D017252:CD3 Complex / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D017252:CD3 Complex; C472562:CD3delta antigen; D022821:RNA Splice Sites; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta