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

Abstract TCR-ab+CD3+CD4-CD8- double negative T cells are expanded in the peripheral blood of patients with systemic lupus erythematosus (SLE) and autoimmune lymphoproliferative syndrome. In both disorders, double negative T cells infiltrate tissues, induce immunoglobulin production and secrete pro-inflammatory 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 transcription factor cAMP responsive element modulator (CREM)α, which is expressed at increased levels in T cells from SLE patients, contributes to transcriptional silencing of CD8A and CD8B. We provide first evidence that CREMα trans-represses a regulatory element 5 of the CD8B gene. Therefore, CREMα represents a promising candidate in the search for biomarkers and treatment options in diseases in which double negative T cells contribute to the pathogenesis.