Impaired translational response and increased protein kinase PKR expression in T cells from lupus patients

Activation of peripheral blood T cells results in a rapid and substantial r ise in translation rates and proliferation, but proliferation in response t o mitogen stimulation is impaired in systemic lupus erythematosus (SLE). We have investigated translation rates and initiation factor activities in T cells from SLE patients in response to activating signals. Activation by PM A plus ionomycin strongly increased protein synthesis in control T cells bu t not in T cells from SLE patients. The rate of protein synthesis is known to be strongly dependent on the activity of two eukaryotic translation init iation factors, eIF4E and eIF2 alpha. We show that following stimulation, e IF4E expression and phosphorylation increased equivalently in control and S LE T cells, Expression of eIF4E interacting proteins - eIF4G, an inducer, a nd 4E-BP1 and 4E-BP2, two specific repressors of eIF4E function - and the p hosphorylation level of 4E-BP1, were all identical in control and SLE T cel ls. In contrast, the protein kinase PKR, which is responsible for the phosp horylation and consequent inhibition of eIF2 alpha activity was specificall y overexpressed in activated SLE T cells, correlating with an increase in e IF2 alpha phosphorylation. Therefore, high expression of PKR and subsequent eIF2 alpha phosphorylation is likely responsible, at least in part, for im paired translational and proliferative responses to mitogens in T cells fro m SLE patients.