Thymocyte selection-associated high mobility group box protein (TOX), a member of the high-motility group box (HMG) protein superfamily, is an evolutionarily conserved DNA-binding protein. It functions as a transcription factor that modulates transcriptional programs by binding to DNA in a structure-dependent manner. It has been well established that TOX is required for the development of CD4⁺ T cells, natural killer (NK) cells and innate lymphoid cells (ILCs), as well as the autoimmunity mediated by CD8⁺ T cells. Recently, emerging evidence supports an essential role for TOX in the induction of T cell exhaustion in the setting of tumor or chronic viral infection by mediating transcriptional and epigenetic changes, which are cardinal hallmarks of exhausted T cells. Moreover, TOX plays a key role in the persistence of antigen-specific T cells and in the mitigation of tissue damage caused by immunopathology over the course of tumorigenesis and chronic infection. Additionally, TOX contributes to the high level of programmed cell death protein 1 (PD-1) on the cell surface by participating in the process of endocytic recycling of PD-1. In this review, we summarize the most recent information about the role of TOX in the process of T cell exhaustion, which enriches our understanding of the molecular mechanisms of CD8⁺ T cell exhaustion upon chronic antigen stimulation and reveals promising therapeutic targets for persisting infection and cancer.

胸腺细胞选择相关的高迁移率组框蛋白( TOX) 是高迁移率组框(HMG) 蛋白超家族的成员，是一种进化上保守的 DNA 结合蛋白。它作为一种转录因子发挥作用，通过以结构依赖性方式与 DNA 结合来调节转录程序。已经确定 TOX 是 CD4 ⁺ T 细胞、自然杀伤 (NK) 细胞和先天淋巴细胞 (ILC) 的发育以及由 CD8 ⁺介导的自身免疫所必需的。T细胞。最近，新出现的证据支持 TOX 通过介导转录和表观遗传变化在肿瘤或慢性病毒感染的情况下诱导 T 细胞衰竭中的重要作用，这是衰竭 T 细胞的主要标志。此外，TOX 在抗原特异性 T 细胞的持久性和减轻肿瘤发生和慢性感染过程中由免疫病理学引起的组织损伤方面发挥着关键作用。此外，TOX 通过参与 PD-1 的内吞循环过程，有助于细胞表面的高水平程序性细胞死亡蛋白 1 (PD-1)。在这篇综述中，我们总结了关于TOX在T细胞耗竭过程中作用的最新信息，丰富了我们对CD8 ⁺分子机制的理解。 慢性抗原刺激后 T 细胞耗竭，并揭示了持续感染和癌症的有希望的治疗靶点。