Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 4, Pages 2361-2370Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.523605
Keywords
Chromatin; Chromatin Histone Modification; DNA Methylation; Epigenetics; Histone Methylation; Histone Modification; CD8; CREM; SLE; Double Negative T Cells
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Funding
- National Institutes of Health [R01 AI42269, R01 AI49954, R01 AI85567]
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TCR-(+)CD3(+)CD4(-)CD8(-) double negative T cells are expanded in the peripheral blood of patients with systemic lupus erythematosus (SLE) and lupus-prone mice. Double negative T cells have been claimed to derive from CD8(+) cells that down-regulate CD8 co-receptors and acquire a distinct effector phenotype that includes the expression of proinflammatory cytokines. This, along with the fact that double negative T cells have been documented in inflamed organs, suggests that they may contribute to disease expression and tissue damage. We recently linked the transcription factor cAMP responsive element modulator (CREM) , which is expressed at increased levels in T cells from SLE patients and lupus prone MRL/lpr mice, with trans-repression of a region syntenic to the murine CD8b promoter. However, the exact molecular mechanisms that result in a stable silencing of both CD8A and CD8B genes remain elusive. Here, we demonstrate that CREM orchestrates epigenetic remodeling of the CD8 cluster through the recruitment of DNA methyltransferase (DNMT) 3a and histone methyltransferase G9a. Thus, we propose that CREM is essential for the expansion of double negative T cells in SLE. CREM blockade may have therapeutic value in autoimmune disorders with DN T cell expansion.
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