Hogan Patrick G, Villalobos Reveles Bruno, Arteaga Vazquez Leo Josue
La Jolla Institute for Immunology, La Jolla, CA, United States.
Moores Cancer Center, University of California-San Diego, La Jolla, CA, United States.
Front Immunol. 2025 Jul 17;16:1576468. doi: 10.3389/fimmu.2025.1576468. eCollection 2025.
The transcription factor TOX has attracted attention in recent years for its role in CD8 T cell exhaustion. In fact, TOX was known historically for its diverse roles in immune cell biology. Here, we inquire into the basis for this versatility, and propose that one main consideration is that TOX is an HMG-box transcription factor. We discuss some mechanisms that other HMG-box transcription factors employ to perform their cellular functions, as examples of the range of mechanisms TOX might employ in furthering T cell exhaustion. This inquiry begins with the literature placing TOX as a central player in CD8 T cell exhaustion and in other immune cell processes. An understanding of TOX as a transcription factor has to be organized around its binding to relevant target sites in DNA. Thus, we next cover the reasons that TOX is classified as an HMG-box protein, the well-defined but narrow scope of what TOX shares with other HMG-box proteins, and the unequivocal evidence that binding of HMG-box proteins stabilizes kinked or bent DNA. We consider the constant features and some variables in DNA recognition by HMG-box proteins. Since binding and bending DNA is not in isolation an explanation of any biological process, we look at biological examples highlighting specific ways that HMG-box proteins drive cellular processes. Finally, we outline some lines of research that could be informative in understanding the cellular mechanisms of TOX in T cell exhaustion.
近年来，转录因子TOX因其在CD8 T细胞耗竭中的作用而备受关注。事实上，TOX在免疫细胞生物学中的多种作用在历史上就已为人所知。在此，我们探究这种多功能性的基础，并提出一个主要的考虑因素是TOX是一种HMG盒转录因子。我们讨论了其他HMG盒转录因子用于执行其细胞功能的一些机制，作为TOX在促进T细胞耗竭中可能采用的机制范围的示例。这项探究始于将TOX视为CD8 T细胞耗竭和其他免疫细胞过程中的核心参与者的文献。对TOX作为转录因子的理解必须围绕其与DNA中相关靶位点的结合来组织。因此，我们接下来阐述TOX被归类为HMG盒蛋白的原因、TOX与其他HMG盒蛋白共有的明确但狭窄的范围，以及HMG盒蛋白结合稳定扭结或弯曲DNA的明确证据。我们考虑HMG盒蛋白识别DNA时的恒定特征和一些变量。由于结合和弯曲DNA本身并不能解释任何生物学过程，我们研究了突出HMG盒蛋白驱动细胞过程的特定方式的生物学实例。最后，我们概述了一些有助于理解TOX在T细胞耗竭中的细胞机制的研究方向。
