cAMP responsive element modulator (CREM) α mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells.
Title | cAMP responsive element modulator (CREM) α mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Hedrich, C. M., Crispín J. C., Rauen T., Ioannidis C., Koga T., Rodriguez N. Rodriguez, Apostolidis S. A., Kyttaris V. C., & Tsokos G. C. |
Journal | J Biol Chem |
Volume | 289 |
Issue | 4 |
Pagination | 2361-70 |
Date Published | 2014 Jan 24 |
ISSN | 1083-351X |
Keywords | Animals, Antigens, CD3, Antigens, CD8, Chromatin Assembly and Disassembly, Cyclic AMP Response Element Modulator, DNA (Cytosine-5-)-Methyltransferase, Female, Gene Silencing, Histocompatibility Antigens, Histone-Lysine N-Methyltransferase, Humans, Lupus Erythematosus, Systemic, Male, Mice, Mice, Inbred MRL lpr, T-Lymphocytes |
Abstract | 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 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) 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 CD8A and 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 methyltransferase G9a. Thus, we propose that CREMα is essential for the expansion of double negative T cells in SLE. CREMα blockade may have therapeutic value in autoimmune disorders with DN T cell expansion. |
DOI | 10.1074/jbc.M113.523605 |
Alternate Journal | J. Biol. Chem. |
PubMed ID | 24297179 |
PubMed Central ID | PMC3900979 |
Grant List | P30 DK043351 / DK / NIDDK NIH HHS / United States R01 AI085567 / AI / NIAID NIH HHS / United States R01 AI42269 / AI / NIAID NIH HHS / United States R01 AI49954 / AI / NIAID NIH HHS / United States R01 AI85567 / AI / NIAID NIH HHS / United States R37 AI049954 / AI / NIAID NIH HHS / United States |