ABSTRACT
T cells recognize antigens via their cell surface TCR and are classified as either αß or γδ depending on the variable chains in their TCR, α and ß or γ and δ, respectively. Both αß 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 αß T cell-specific defect. Here, we report 2 unrelated cases of SCID with a selective block in αß 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 αß 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 αß T cells, surface TCR expression was more reduced in γδ than in αß T cells. Analysis of individuals with this CD3D mutation thus demonstrates the contrasting CD3δ requirements for αß 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.
Subject(s)
CD3 Complex/genetics , Mutation , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/immunology , T-Lymphocyte Subsets/immunology , Animals , B-Lymphocytes/immunology , Base Sequence , DNA Mutational Analysis , Female , Humans , Infant , Killer Cells, Natural/immunology , Male , Mice , Pedigree , RNA Splice Sites/genetics , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Severe Combined Immunodeficiency/etiologyABSTRACT
A case-control study was performed to assess whether T-cell activation profile of CD8+ T-cells is associated with unexplained recurrent abortion. Women with abortion had significantly higher percentages (32 +/- 11 vs. 24 +/- 13%) and absolute numbers (160 +/- 78 vs. 114 +/- 83 cells/mm(3)) of CD8+DR+ T-cells than controls.
