Abstract
T cell receptor-αβ(+) 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 α (CREMα), 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 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.
Highlights
Expanded CD3ϩCD4ϪCD8Ϫ T cells in Systemic lupus erythematosus (SLE) originate from CD8ϩ T cells
We demonstrate that the transcription factor cAMP-responsive element modulator ␣ (CREM␣), which is expressed at increased levels in T cells from systemic lupus erythematosus patients, contributes to transcriptional silencing of CD8A and CD8B
Changes in gene expression in response to T cell receptor (TCR) stimulation are displayed as an increase (Ͼ1) or decrease (Ͻ1) over CD8 expression in resting CD8ϩ T cells
Summary
Expanded CD3ϩCD4ϪCD8Ϫ T cells in SLE originate from CD8ϩ T cells. Results: CREM␣ trans-represses CD8 gene transcription. T cell receptor-␣؉ 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. We demonstrate that the transcription factor cAMP-responsive element modulator ␣ (CREM␣), which is expressed at increased levels in T cells from systemic lupus erythematosus patients, contributes to transcriptional silencing of CD8A and CD8B. We present evidence that CD8ϩ T cells down-regulate CD8 surface expression in response to TCR stimulation through transcriptional silencing of the CD8A and CD8B genes. CREM␣ represents the first described transcription factor to trans-repress CD8 gene expression
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