cAMP responsive element modulator (CREM)α mediates chromatin remodeling of CD8 during the generation of CD3+CD4-CD8- T cells
2014
TCR-αβ+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 negativeT cells have been claimed to derive from CD8+ cells that down-regulate CD8
co-receptorsand acquire a distinct effector phenotype that includes the expression of proinflammatory cytokines. This, along with the fact that
double negativeT 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) α, 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
CD8Aand CD8B genes remain elusive. Here, we demonstrate that CREMα orchestrates epigenetic remodeling of the CD8 cluster through the recruitment of
DNA methyltransferase(DNMT) 3a and
histone methyltransferaseG9a. Thus, we propose that CREMα is essential for the expansion of
double negativeT cells in SLE. CREMα blockade may have therapeutic value in autoimmune disorders with DN T cell expansion.
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