Abstract
Interleukin-7 receptor α (IL-7Rα) is essential for T cell survival and differentiation. Glucocorticoids are potent enhancers of IL-7Rα expression with diverse roles in T cell biology. Here we identify the transcriptional repressor, growth factor independent-1 (Gfi1), as a novel intermediary in glucocorticoid-induced IL-7Rα up-regulation. We found Gfi1 to be a major inhibitory target of dexamethasone by microarray expression profiling of 3B4.15 T-hybridoma cells. Concordantly, retroviral transduction of Gfi1 significantly blunted IL-7Rα up-regulation by dexamethasone. To further assess the role of Gfi1 in vivo, we generated bacterial artificial chromosome (BAC) transgenic mice, in which a modified Il7r locus expresses GFP to report Il7r gene transcription. By introducing this BAC reporter transgene into either Gfi1-deficient or Gfi1-transgenic mice, we document in vivo that IL-7Rα transcription is up-regulated in the absence of Gfi1 and down-regulated when Gfi1 is overexpressed. Strikingly, the in vivo regulatory role of Gfi1 was specific for CD8(+), and not CD4(+) T cells or immature thymocytes. These results identify Gfi1 as a specific transcriptional repressor of the Il7r gene in CD8 T lymphocytes in vivo.
Highlights
Expression of the IL-7 receptor (IL-7R)␣ gene is up-/down-regulated during T/B-lymphocyte development
We identified growth factor independent-1 (Gfi1) as a novel target of Dex and we further documented that either Gfi1 overexpression or treatment with the glucocorticoid receptor (GR) inhibitor RU486 (Mifepristone) in 3B4.15 cells prevented IL-7R␣ up-regulation by Dex
double positive (DP) thymocytes, which express high levels of Gfi1 and are completely silent for IL-7R␣ transcription, were still negative for GFP expression, when Gfi1 expression was ablated. These results indicate that Gfi1 is not required to suppress IL-7R␣ expression in this particular subset
Summary
Expression of the IL-7R␣ gene is up-/down-regulated during T/B-lymphocyte development. To further assess the role of Gfi in vivo, we generated bacterial artificial chromosome (BAC) transgenic mice, in which a modified Il7r locus expresses GFP to report Il7r gene transcription. 34386 JOURNAL OF BIOLOGICAL CHEMISTRY ingly, the in vivo regulatory role of Gfi was specific for CD8؉, and not CD4؉ T cells or immature thymocytes These results identify Gfi as a specific transcriptional repressor of the Il7r gene in CD8 T lymphocytes in vivo. FoxP3 was found to bind near the promoter in Treg cells to suppress IL-7R␣ transcription [22] How these factors interact with each other and what controls the mechanism of developmental stage-specific differences in Il7r gene transcription remains ill defined. To further assess the role of Gfi in vivo, we generated a novel bacterial artificial chromosome (BAC) transgenic mouse that reports transcriptional activity of the Il7r gene locus. Our observations place Gfi as a lineagespecific and developmental stage-dependent transcriptional repressor of IL-7R␣ in vivo
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