title: Membrane and transmembrane signaling in Herpesvirus saimiri-transformed human CD4(+) and CD8(+) T lymphocytes is ATM-independent.
abstract: In the genetic disorder ataxia telangiectasia (AT), humoral (B) and cellular (T) immunological abnormalities are frequently observed. As a consequence, AT patients are predisposed to life-threatening sinopulmonary infections. The pathogenic mechanisms remain unknown, but a role for ATM in signal transduction from membrane receptors has been proposed. We have explored the effects of a defective ATMgene on isolated human T-lineage cells from 13 AT patients with proven T cell dysfunction by transforming their CD4(+) and CD8(+) T lymphocytes with Herpesvirus saimiri, and analyzing their signaling behavior as compared to normal controls. Several functional parameters were assayed in response to both membrane (anti-CD3 and IL-2) and transmembrane (phorbol myristate acetate plus the calcium ionophore ionomycin) stimuli: (i) calcium mobilization, (ii) induction of activation molecules (CD25, CD40 ligand, CD69 and CD71), (iii) cytokine synthesis (IL-2 and tumor necrosis factor-alpha) and (iv) proliferation. All these early and late activation events were found to be normal in the transformed ATM-/-T cells, indicating that ATM is not necessary for their induction. As expected, ATM-/- transformed T cells showed an increased radiosensitivity by both radioresistant DNA synthesis and cell survival assays. In contrast to an earlier report testing transformed B lymphocytes, our results indicate that transformed mature peripheral T lymphocytes from AT patients do not have intrinsic immune function defects. Rather, the described T-lineage signaling impairments observed in patients may be secondary in vivo to extrinsic ATM-dependent suppressive factors and/or to a developmental defect. These transformed T cells may help to understand the distinct biological role of ATM in different cell types and to develop rational therapies for the immunological dysfunction of AT patients.
authors.affiliation: Inmunología, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Rivero-Carmena
authors.forename: O
authors.initials: O
authors.lastname: Porras
authors.forename: B
authors.initials: B
authors.lastname: Pelaez
authors.forename: A
authors.initials: A
authors.lastname: Pacheco-Castro
authors.forename: R A
authors.initials: RA
authors.lastname: Gatti
authors.forename: J R
authors.initials: JR
authors.lastname: Regueiro
mesh_terms: D000293:Adolescent; D001260:Ataxia Telangiectasia / Q000276:immunology*; D064007:Ataxia Telangiectasia Mutated Proteins; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D018797:Cell Cycle Proteins; D002472:Cell Transformation, Viral; D002648:Child; D004268:DNA-Binding Proteins; D006567:Herpesvirus 2, Saimiriine / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011836:Radiation Tolerance; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases