A primary T-cell immunodeficiency associated with defective transmembrane calcium influx
| Autor: | Le Deist F, Claire Hivroz, Partiseti M, Thomas C, Ha, Buc, Oleastro M, Belohradsky B, Choquet D, Fischer A |
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| Předmět: |
Male
Receptors Antigen T-Cell alpha-beta T-Lymphocytes Molecular Sequence Data Lymphocyte Activation Phosphatidylinositols Proto-Oncogene Proteins c-fyn Immunophenotyping Substrate Specificity Antigens CD Reference Values Proto-Oncogene Proteins Humans Phosphotyrosine Phospholipids Cell Nucleus Base Sequence Ionomycin Cell Membrane Immunologic Deficiency Syndromes Infant Biological Transport Protein-Tyrosine Kinases DNA-Binding Proteins Oligodeoxyribonucleotides Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Interleukin-2 Tyrosine Calcium |
| Zdroj: | Europe PubMed Central |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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