cAMP-responsive Element Modulator α (CREMα) trans-Represses the Transmembrane Glycoprotein CD8 and Contributes to the Generation of CD3+CD4-CD8- T Cells in Health and Disease

T cell receptor-alpha beta(+) CD3(+)CD4(-)CD8(-) double-negative T cells are expanded in the peripheral blood of patients with systemic lupus erythematosus and autoimmune lymphoproliferative syndrome. In both disorders, double-negative T cells infiltrate tissues, induce immunoglobulin production, and secrete proinflammatory cytokines. Double-negative T cells derive from CD8(+) T cells through down-regulation of CD8 surface co-receptors. However, the molecular mechanisms orchestrating this process remain unclear. Here, we demonstrate that the transcription factor cAMP-responsive element modulator alpha (CREM alpha), which is expressed at increased levels in T cells from systemic lupus erythematosus patients, contributes to transcriptional silencing of CD8A and CD8B. We provide the first evidence that CREM alpha trans-represses a regulatory element 5' of the CD8B gene. Therefore, CREM alpha represents a promising candidate in the search for biomarkers and treatment options in diseases in which double-negative T cells contribute to the pathogenesis.