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Abstract：
Tox is a member of the high mobility group (HMG)-Box transcription factors and plays important roles in thymic T cell development. Outside of the thymus, however, Tox is also highly expressed by CD8 and CD4 T cells in various states of activation and in settings of cancer and autoimmune disease. In CD4 T cells, Tox has been primarily studied in T follicular helper (TFH) cells where it, along with Tox2, promotes TFH differentiation by regulating key TFH-associated genes and suppressing CD4 cytotoxic T cell differentiation. However, the role of Tox in other T helper (Th) cell subtypes is less clear. Here, we show that Tox is expressed in several physiologically-activated Th subtypes and its ectopic expression enhances the in vitro differentiation of Th2 and T regulatory (Treg) cells. Tox overexpression in unpolarized Th cells also induced the expression of several genes involved in cell activation (Pdcd1), cellular trafficking (Ccl3, Ccl4, Xcl1) and suppressing inflammation (Il10) across multiple Th subtypes. We found that Tox binds the regulatory regions of these genes along with the transcription factors BATF, IRF4, and JunB and that Tox-induced expression of IL-10, but not PD-1, is BATF-dependent. Based on these data, we propose a model where Tox regulates Th cell chemotactic genes involved in facilitating dendritic cell-T cell interactions and aids in the resolution or prevention of inflammation through the production of IL-10.
摘要：
Tox是高迁移率族（HMG）-Box转录因子的成员，在胸腺T细胞发育中起重要作用。在胸腺之外,然而,Tox也在各种活化状态下以及在癌症和自身免疫性疾病的背景下由CD8和CD4T细胞高度表达。在CD4T细胞中，毒性已主要在T滤泡辅助（TFH）细胞中进行了研究，与Tox2一起，通过调节关键TFH相关基因和抑制CD4细胞毒性T细胞分化来促进TFH分化。然而,Tox在其他T辅助（Th）细胞亚型中的作用尚不清楚。这里,我们表明Tox在几种生理激活的Th亚型中表达，其异位表达增强了Th2和T调节（Treg）细胞的体外分化。Tox在非极化Th细胞中的过表达也诱导了几种参与细胞活化的基因（Pdcd1）的表达，跨多个Th亚型的细胞运输(Ccl3、Ccl4、Xcl1)和抑制炎症(Il10)。我们发现Tox与转录因子BATF结合在这些基因的调控区，IRF4和JunB以及Tox诱导的IL-10而不是PD-1的表达是BATF依赖性的。基于这些数据,我们提出了一个模型,其中Tox调节参与促进树突状细胞-T细胞相互作用的Th细胞趋化基因,并通过IL-10的产生帮助解决或预防炎症.
