IL-7 suppresses CD127 gene transcription in human CD8 T cells by inducing expression of the transcription factor c-Myb (P6299)

Abstract

In view of the role interleukin (IL)-7 plays in T cell survival, homeostasis and function it is no surprise expression of the IL-7 receptor-α (CD127) is tightly regulated. Dysregulation of IL-7 signaling and CD127 expression has been implicated in a number of diseases such as multiple sclerosis, breast cancer, arthritis as well as in HIV infection. Thus it is important to understand how IL-7 regulates its own receptor expression. Here we elucidate the mechanism by which IL-7 suppresses CD127 transcripts in primary human CD8 T cells. We show by qPCR and nuclear run-on assays that IL-7 suppresses CD127 gene transcription in a time- and dose-dependent manner. The IL-7 mediated suppression of CD127 transcripts is dependent on JAK/STAT5 signaling. Notably, cycloheximide blocked IL-7’s ability to down-regulate CD127 transcripts suggesting IL-7 stimulates the de novo synthesis of a transcriptional repressor which in turn suppresses CD127 gene transcription. Through DNA microarrays and PCR arrays, the IL-7 inducible transcription factor c-Myb was identified. The region within the CD127 gene promoter required for IL-7 mediated transcriptional suppression was identified through progressive truncations using firefly luciferase as a reporter gene and is located from -1760 to -2406 bp upstream of the TATA box and contains c-Myb binding sites. Using siRNA-mediated knockdown and transient over-expression, we illustrate c-Myb suppresses CD127 gene transcription in primary human CD8 T cells.