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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.

journal_name

Int Immunol

journal_title

International immunology

authors

Rivero-Carmena M,Porras O,Pelaez B,Pacheco-Castro A,Gatti RA,Regueiro JR

doi

10.1093/intimm/12.6.927

subject

Has Abstract

pub_date

2000-06-01 00:00:00

pages

927-35

issue

eissn

0953-8178

issn

1460-2377

journal_volume

pub_type

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Membrane and transmembrane signaling in Herpesvirus saimiri-transformed human CD4(+) and CD8(+) T lymphocytes is ATM-independent.