title: A primary T-cell immunodeficiency associated with defective transmembrane calcium influx.
abstract: We investigated a T-cell activation deficiency in a 3-month-old boy with protracted diarrhea, serious cytomegalovirus pneumonia, and a family history (in a brother) of cytomegalovirus infection and toxoplasmosis. In spite of detection of normal number of peripheral lymphocytes, T cells did not proliferate after activation by anti-CD3 and anti-CD2 antibodies, although proliferation induced by antigens was detectable. We sought to determine the origin of this defect as it potentially represented a valuable tool to analyze T-cell physiology. T-cell activation by anti-CD3 antibody or phytohemagglutinin (PHA) led to reduced interleukin-2 (IL-2) production and abnormal nuclear factor-activated T cell (NF-AT; a complex regulating the IL-2 gene transcription) binding activity to a specific oligonucleotide. T-cell proliferation was restored by IL-2. Early events of T-cell activation, such as anti-CD3 antibody-induced cellular protein tyrosine phosphorylation, p59fyn and p56lck kinase activities, and phosphoinositide turnover, were found to be normal. In contrast, anti-CD3 antibody-induced Ca2+ flux was grossly abnormal. Release from endoplasmic reticulum stores was detectable as tested in the presence of anti-CD3 antibody or thapsigargin after cell membrane depolarization in a K+ rich medium, whereas extracellular entry of Ca2+ was defective. The latter abnormality was not secondary to defective K+ channel function, which was found to be normal. A similar defect was found in other hematopoietic cell lineages and in fibroblasts as evaluated by both cytometry and digital video imaging experiments at a single-cell level. This primary T-cell immunodeficiency appears, thus, to be due to defective Ca2+ entry through the plasma membrane. The same abnormality did not alter B-cell proliferation, platelet function, and polymorphonuclear neutrophil (PMN) function. Elucidation of the mechanism underlying this defect would help to understand the physiology of Ca2+ mobilization in T cells.
authors.affiliation: INSERM U132, Hôpital Necker Enfants Malades, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Le Deist
authors.forename: C
authors.initials: C
authors.lastname: Hivroz
authors.forename: M
authors.initials: M
authors.lastname: Partiseti
authors.forename: C
authors.initials: C
authors.lastname: Thomas
authors.forename: H A
authors.initials: HA
authors.lastname: Buc
authors.forename: M
authors.initials: M
authors.lastname: Oleastro
authors.forename: B
authors.initials: B
authors.lastname: Belohradsky
authors.forename: D
authors.initials: D
authors.lastname: Choquet
authors.forename: A
authors.initials: A
authors.lastname: Fischer
mesh_terms: D015703:Antigens, CD / Q000097:blood; D001483:Base Sequence; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000097:blood / Q000276:immunology*; D016130:Immunophenotyping; D007223:Infant; D007376:Interleukin-2 / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008297:Male; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D010716:Phosphatidylinositols / Q000097:blood; D010743:Phospholipids / Q000378:metabolism; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D012016:Reference Values; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
chemical_list: D015703:Antigens, CD; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D009838:Oligodeoxyribonucleotides; D010716:Phosphatidylinositols; D010743:Phospholipids; D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019000:Phosphotyrosine; D014443:Tyrosine; D015759:Ionomycin; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D002118:Calcium