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Expression of deoxyadenosine and deoxyguanosine toxicity at different stages of lymphocyte activation
J G Scharenberg1, G T Rijkers, E A Toebes
1Department of Immunology, University Hospital for Children and Youth, Utrecht, The Netherlands.
Abstract:
We have previously shown that deoxyguanosine (dGuo) is toxic to normal T and B lymphocytes, an effect mediated by intracellular accumulation of guanine ribonucleotides. In order to define the cellular processes that are sensitive to guanosine triphosphate (GTP) we have performed studies in which the effects of dGuo on normal T cells are compared with those of deoxyadenosine (dAdo) on adenosine deaminase (ADA)-deficient T cells. Kinetic studies show that dAdo exerts its toxic effects on processes that precede the onset of DNA synthesis, like interleukin 2 receptor expression, whereas dGuo added as late as 24-48 h after initiation of the culture still inhibits mitogen-induced proliferation. It can thus be concluded that dGuo toxicity as mediated through guanine ribonucleotides is manifested relatively late during the process of T-cell activation, whereas dAdo acts early in T-cell activation by a mechanism that cannot be explained by inhibition of ribonucleotide reductase.
Insights
Deoxyguanosine (dGuo) toxicity impacts T-cell activation late, affecting proliferation. Deoxyadenosine (dAdo) toxicity affects early T-cell activation, influencing interleukin 2 receptor expression.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Deoxyguanosine (dGuo) is toxic to T and B lymphocytes, mediated by guanine ribonucleotides.
- Understanding cellular processes sensitive to guanosine triphosphate (GTP) is crucial.
Purpose of the Study:
- To define cellular processes sensitive to guanosine triphosphate (GTP).
- To compare the effects of dGuo on normal T cells with dAdo on adenosine deaminase (ADA)-deficient T cells.
Main Methods:
- Kinetic studies comparing dGuo and dAdo effects on T-cell activation.
- Analysis of T-cell proliferation and interleukin 2 receptor expression.
Main Results:
- dAdo toxicity affects early T-cell activation, including interleukin 2 receptor expression.
- dGuo toxicity manifests late, inhibiting mitogen-induced proliferation even 24-48 hours after culture initiation.
- dAdo's mechanism is independent of ribonucleotide reductase inhibition.
Conclusions:
- dGuo toxicity impacts late T-cell activation stages.
- dAdo toxicity affects early T-cell activation stages through a novel mechanism.