title: Aberrant T-cell receptor signalling of interferon-gamma- and tumour necrosis factor-alpha-producing cytotoxic CD8+ Vdelta1/Vbeta16 T cells in a patient with chronic neutropenia.
abstract: We previously found that the peripheral blood (PB) mononuclear cells (MCs) (PBMCs) of a patient with chronic neutropenia contained an expanded population of cytotoxic CD8+ T cells using a variable (V) region delta1 gene product in the T-cell receptor-alpha (TCR-alpha) polypeptide [Vdelta1-constant(C)alpha+ T cells]. Sequencing of polymerase chain reaction (PCR) amplification products have now revealed a productive Vdelta1/joining (J)alphaIGRJa03/Calpha rearrangement of the TCR-alpha gene, predominantly associated with a Vbeta16/Dbeta2.1/Jbeta2.1/Cbeta2 TCR-beta gene, in these cells. Furthermore, we detected a markedly deficient proliferative response of the patient PBMCs to triggering with monoclonal antibodies (MoAbs) to the CD3 molecule, contrasting with a substantial response to the Vbeta3, 12, 14, 15, 17 and 20-specific staphylococcal enterotoxin B (SEB) superantigen, suggesting defective TCR-mediated activation of the Vdelta1+/Vbeta16+ clone. Moreover, whereas triggering of Vdelta1- T cells cultured with interleukin-2 (IL-2) by MoAb to the CD3 molecule enhanced proliferation, Vdelta1-Calpha+ T cells were inhibited by MoAbs to either CD3 or Vdelta1. Vdelta1-Calpha+ T-cell clones spontaneously secrete interferon-gamma (IFN-gamma) and were further induced to release tumour necrosis factor (TNF-alpha) when triggered by anti-CD3 plus phorbol ester. Aberrant signalling by the clonotypic TCR together with the functional properties of the CD8+ Vdelta1+/Vbeta16+ clone may thus contribute to the immunohaematological abnormalities observed in this patient.
authors.affiliation: Department of Medicine F, Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel. ibank@post.tau.ac.il
authors.forename: I
authors.initials: I
authors.lastname: Bank
authors.forename: L
authors.initials: L
authors.lastname: Cohen
authors.forename: A
authors.initials: A
authors.lastname: Kneller
authors.forename: N K
authors.initials: NK
authors.lastname: De Rosbo
authors.forename: M
authors.initials: M
authors.lastname: Book
authors.forename: A
authors.initials: A
authors.lastname: Ben-Nun
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017252:CD3 Complex / Q000276:immunology; D002908:Chronic Disease; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000096:biosynthesis; D008969:Molecular Sequence Data; D009503:Neutropenia / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D017252:CD3 Complex; D008222:Lymphokines; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma