BCL11B enhances TCR/CD28-triggered NF-kB activation through upregulation of Cot kinase gene expression in T lymphocytes

BCL11B is a transcriptional regulator with important role in T cell development and leukemogenesis. Recently we demonstrated that BCL11B controls expression from IL-2 promoter through direct binding to the US1 site. Here we provide evidence that BCL11B also participates in the activation of IL-2 gene expression by enhancing NF-kB activity in the context of TCR/CD28–triggered T cell activation. Enhanced NF-kB activation is not a consequence of BCL11B binding to the NF-kB response elements or association with the NF-kB-DNA complexes, but rather the result of higher translocation of NF-kB to the nucleus caused by enhanced degradation of the IkB. The enhanced IkB degradation in cells with increased levels of BCL11B was specific for T cells activated through TCR, but not through TNFα or UV, and was caused by higher activity of IkB kinase, as indicated by its higher phosphorylation. As BCL11B is a transcription factor we investigated whether expression of genes upstream of IkB kinase in the TCR/CD28 signaling pathway was affected by increased BCL11B expression, and found that Cot kinase mRNA levels were elevated. Cot kinase is known to promote enhanced IkB kinase activity which results in phosphorylation and degradation of the IkB inhibitors and activation of NF-kB. Implication of Cot kinase in BCL11B-mediated NF-kB activation in response TCR activation is supported by the fact that a Cot kinase dominant negative mutant or Cot kinase siRNA blocked BCL11B-mediated NF-kB activation. In support of our observations, we report that BCL11B enhances expression of several other NF-kB target genes, in addition to IL-2. In addition, we provide evidence that BCL11B associates with Cot kinase gene intron 2 to regulate its expression.