Wildt Kathryn F, Sun Guangping, Grueter Baerbel, Fischer Maria, Zamisch Monica, Ehlers Marc, Bosselut Rémy
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2007 Oct 1;179(7):4405-14. doi: 10.4049/jimmunol.179.7.4405.
The persistence of CD4 expression is a key event distinguishing the differentiation of MHC class II-restricted thymocytes into CD4 T cells from that of MHC class I-restricted thymocytes into CD8 T cells. The zinc finger transcription factor Zbtb7b (or cKrox or Thpok) is normally expressed in MHC class II-restricted thymocytes and promotes CD4 lineage choice. When expressed in MHC class I-restricted cells, Zbtb7b redirects these cells from their normal CD8 fate to CD4 differentiation, implying that it promotes, directly or not, sustained CD4 expression; the present study has investigated the mechanism of this effect. We demonstrate that, although Zbtb7b does not enhance CD4 expression on its own, it antagonizes the CD4 repression mediated by the transcription factor Runx3, which is normally up-regulated during CD8 differentiation and promotes CD4 silencing. Zbtb7b also antagonizes CD4 repression by the related protein Runx1, which is expressed in CD4 lineage cells. This antagonism is observed both in vitro and in vivo, is transcriptional, and requires domains of Zbtb7b that are essential to its ability to promote CD4 differentiation in vivo. Furthermore, Zbtb7b fails to antagonize Runx in cells treated with histone deacetylase inhibitors, suggesting that Zbtb7b acts by reducing the expression of thus far unknown factors that cooperate with Runx molecules to repress CD4. These findings demonstrate that the transcription factor Zbtb7b promotes CD4 expression by antagonizing Runx-mediated CD4 repression.
CD4表达的持续存在是区分MHC II类限制性胸腺细胞分化为CD4 T细胞与MHC I类限制性胸腺细胞分化为CD8 T细胞的关键事件。锌指转录因子Zbtb7b（或cKrox或Thpok）通常在MHC II类限制性胸腺细胞中表达，并促进CD4谱系选择。当在MHC I类限制性细胞中表达时，Zbtb7b将这些细胞从其正常的CD8命运重定向为CD4分化，这意味着它直接或间接地促进了CD4的持续表达；本研究调查了这种作用的机制。我们证明，虽然Zbtb7b本身不会增强CD4表达，但它拮抗转录因子Runx3介导的CD4抑制，Runx3通常在CD8分化过程中上调并促进CD4沉默。Zbtb7b还拮抗相关蛋白Runx1对CD4的抑制，Runx1在CD4谱系细胞中表达。这种拮抗作用在体外和体内均观察到，是转录性的，并且需要Zbtb7b中对其在体内促进CD4分化能力至关重要的结构域。此外，在用组蛋白去乙酰化酶抑制剂处理的细胞中，Zbtb7b无法拮抗Runx，这表明Zbtb7b通过降低与Runx分子协同抑制CD4的未知因子的表达来发挥作用。这些发现表明，转录因子Zbtb7b通过拮抗Runx介导的CD4抑制来促进CD4表达。
