TOX2 regulates human natural killer cell development by controlling T-BET expression. Homo sapiens

Thymocyte selection-associated high mobility group box protein family member 2 (TOX2) is a transcription factor belonging to the TOX family that shares a highly conserved high mobility group DNA binding domain with the other TOX members. While TOX1 has been shown to be an essential regulator of T-cell and natural killer (NK) cell differentiation in mice, little is known about the roles of the other TOX family members in lymphocyte development, particularly in humans. In this study, we found that TOX2 was preferentially expressed in mature human NK cells and was upregulated during in vitro differentiation of NK cells from human umbilical cord blood (UCB)–derived CD34+ cells. Gene silencing of TOX2 intrinsically hindered the transition between early developmental stages of NK cells, while overexpression of TOX2 enhanced the development of mature NK cells from UCB CD34+ cells. We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). Overexpression of T-BET rescued the TOX2 knockdown phenotypes. Given the essential function of T-BET in NK cell differentiation, TOX2 therefore plays a crucial role in controlling normal NK cell development by acting upstream of TBX21 transcriptional regulation. Overall design: survey of NK cells over time

胸腺细胞选择相关高迁移率族盒蛋白家族成员2（Thymocyte selection-associated high mobility group box protein family member 2, TOX2）是隶属于TOX家族的转录因子，与该家族其他成员共享高度保守的高迁移率族DNA结合结构域。已有研究证实，TOX1是小鼠T细胞与自然杀伤（natural killer, NK）细胞分化的关键调控因子，但目前对于TOX家族其他成员在淋巴细胞发育中的功能，尤其是在人类中的相关功能，仍知之甚少。本研究发现，TOX2在成熟人类NK细胞中呈优先表达模式，且在人类脐带血（human umbilical cord blood, UCB）来源的CD34+细胞体外分化为NK细胞的过程中表达上调。对TOX2进行基因沉默会内在地阻碍NK细胞早期发育阶段的进程转换，而过表达TOX2则可促进UCB来源CD34+细胞向成熟NK细胞的分化发育。后续研究表明，TOX2的调控不依赖于ETS-1，却可直接上调编码T-BET的TBX21的转录水平；过表达T-BET能够挽救TOX2敲低所引发的表型缺陷。鉴于T-BET在NK细胞分化中的核心功能，TOX2可通过作用于TBX21转录调控的上游通路，在正常NK细胞发育的调控中发挥关键作用。整体实验设计：对NK细胞进行时序性全景分析