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.

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…While these processes typically depend on cognate help provided by follicular B helper T (T FH ) cells [97,98], early studies in TCRa À/À and TCRb À/À mice demonstrated that lymph nodes in animals lacking ab T cells still contain germinal centers [99][100][101]. Similarly, patients with selective deficiencies in ab T cells due to mutations in recombinase activating gene 1 (RAG1), TCRa subunit constant gene (TRAC) or CD3D show normal or even elevated levels of antibody production [102][103][104]. Functional proof that cd T cells are sufficient to orchestrate follicular responses came from adoptive transfer experiments in SCID mice [105,106].…”

Hemophagocytic lymphohistiocytosis in a patient with CD3δ deficiency

“…Neither child had obvious features of HLH reported. A leaky type of CD3δ deficiency has been discovered in Ecuadorian children (Gil et al 2011). Unlike the original cases, these patients had normal numbers of circulating TCRγδ + cells but reduced TCRαβ + cells.…”

Severe Combined Immunodeficiency Disorders

“…In the United States, most cases of B-positive, NK-positive SCID occur as a result of IL7R (IL-7Ra) deficiency. 9,24 Rarer defects in components of the T-cell receptor have also been reported to cause SCID, including mutations in CD3D, [25][26][27][28] CD3E, 26 and CD247, 29,30 which encode the CD3 d, ε, and z chains, respectively. Defects in CD3G 31, 32 have not yet been observed to cause true SCID.…”