Increased adenosine deaminase (ADA) activity and a shift from ADA-dependent to ADA-independent phases during T-cell activation: a paradox.
During activation of WF rat splenic T-cells, a change occurs with respect to susceptibility to a toxic accumulation of adenosine or deoxyadenosine (dADO) in the presence of adenosine deaminase (ADA) blockade. Addition of nucleoside 1 hour after the initiation of a concanavalin A response in the presence of 2'deoxycoformycin (DCF) markedly inhibited the response, whereas delay of addition of the nucleoside for 24-48 hours resulted in minimal or no inhibition. Inhibition was not simply the result of prolonged incubation of cells in the presence of nucleoside and was apparently not attributable to an effect on proliferating cells. Addition of interleukin 2 (IL-2) to cultures containing DCF and dADO did not reverse the inhibitory effect, which suggests that IL-2-producing T-cells also were not the target of nucleoside toxicity. A twofold increase in ADA activity that occurred during T-cell activation was nonessential for the survival of mitogen-activated T-cells in the presence of toxic concentrations of dADO and did not account for an apparent increased resistance of these cells to nucleoside toxicity. These paradoxical observations prompted an analysis of ADA activity in various populations of activated T-cells enriched with cells in G0/G1, S, or G2+M cell-cycle phases, which indicated that increased ADA activity was not associated with a specific period during cell-cycle traverse, but, rather, coincided with cell enlargement in preparation for mitosis. In conclusion, either an early event in T-cell mitogenesis is highly susceptible to nucleoside toxicity or a mechanism independent of ADA is acquired during T-cell activation that allows proliferating T-cells to resist toxic concentrations of nucleoside.
D000241:Adenosine / Q000378:metabolism / Q000633:toxicity*; D000243:Adenosine Deaminase / Q000032:analysis*; D000818:Animals; D002453:Cell Cycle; D003208:Concanavalin A / Q000494:pharmacology; D003839:Deoxyadenosines / Q000633:toxicity*; D008658:Inactivation, Metabolic; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D009700:Nucleoside Deaminases / Q000032:analysis*; D051381:Rats; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000187:drug effects*
D003839:Deoxyadenosines; D003208:Concanavalin A; D009700:Nucleoside Deaminases; D000243:Adenosine Deaminase; D000241:Adenosine