Lymphocyte studies in 2 affected children with the SCID disorder We describe 2 SCID cases with severe selective αβ T lymphopenia (Tαβ –Tγδ +B +NK +) caused by a leaky mutation in CD3D that titrated the differential CD3δ requirements for human αβ and γδ T lymphocyte development and TCR expression in vivo. However, no selective αβ or γδ T cell–deficient patients have been reported for invariant TCR chain deficiencies. These immunophenotypes are described as T –B +NK + or T ☛ +NK +, respectively. When an invariant chain is affected, both αβ and γδ T cells are either absent, as observed in CD3δ or CD3ε deficiency ( 4, 5), or reduced, as reported for CD3γ or TCRζ deficiency ( 6, 7). When a variable chain such as TCRα is affected, only αβ T cells are impaired, as shown recently ( 3). Unless hematopoietic stem cells are replaced, the mutations frequently cause early-onset SCID and death. Mutations in TCR or CD3 genes selectively impair T cell development ( 2). Data represent mean ± SD of at least 2 experiments, relative to the highest value in each data set, which is shown as 1. ( F) WT and ΔEx2 CD3D transcript levels relative to CD3E by quantitative RT-PCR in PBMCs using exon-specific primers and isoform-specific probes. Solid symbols denote homozygosity half-solid symbols denote heterozygosity. Circles indicate females squares indicate males (slashes indicate deceased). Exon/intron sequences are in upper/lower case, respectively. ( D) CD3D electropherograms showing the IVS2+5G→A mutation (arrow) in patient AIII.1 (left) and his father (right), and the BsaAI restriction site. ΔEx2 bands lack exon 2 ( C) CD3δ protein and gene structure with localization of the G→A mutation. ( B) CD3D RNA RT-PCR amplification products. EC, extracellular region TM, transmembrane region Cyto, cytoplasmic region. ( A) Structure of the 2 TCR that incorporate the CD3δ chain (arrows). 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. Strikingly, despite the specific loss of αβ T cells, surface TCR expression was more reduced in γδ than in αβ T cells. T cell–dependent B cell functions were also impaired, despite the presence of normal B cell numbers. 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. The patients’ T cells showed reduced CD3D transcripts, CD3δ proteins, surface TCR, and early TCR signaling. 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. However, CD3δ-KO mice have an αβ T cell–specific defect. Consistent with this, all CD3δ-deficient patients described to date showed a complete block in T cell development. 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. Both αβ and γδ TCRs also contain several invariant chains, including CD3δ, which support surface TCR expression and transduce the TCR signal. 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.
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