TOX, also known as thymocyte selection-associated high mobility group box protein, is a DNA-binding protein belonging to an evolutionarily conserved family. It contains a DNA-binding domain and plays crucial roles in the immune system. TOX is involved in regulating T-cell differentiation, and its expression is associated with pathways such as chronic T-cell receptor stimulation and NFAT activation. It is important in various biological processes related to T-cells, including their exhaustion and survival, and has implications for cancer, chronic infections, and autoimmune diseases [1,2,3,4].

In tumor-specific CD8 T cells, deletion of Tox abrogated the exhaustion program as Tox-deleted TST cells did not upregulate genes for inhibitory receptors and retained high expression of transcription factors like TCF-1. However, despite their non-exhausted immunophenotype, these cells remained dysfunctional and failed to persist in tumors, suggesting a decoupling of inhibitory receptor regulation from effector function loss [1]. In autoimmune hepatitis, dual-stage loss of TOX in thymocytes hierarchically impaired mTEC maturation, promoted thymic IL-17A-producing γδ T-cell lineage commitment, and led to the development of fatal autoimmune hepatitis. Transfer of γδ T cells from TOX-deficient mice reproduced AIH, and TOX expression was downregulated in γδ T cells from AIH patients, inversely correlated with the AIH diagnostic score [5].

In conclusion, TOX is a key regulator in T-cell differentiation. Gene knockout models of Tox in mice have revealed its significance in tumor-specific T-cell exhaustion and autoimmune hepatitis. Understanding TOX's functions through these models provides insights into the mechanisms of cancer and autoimmune diseases, potentially guiding the development of new therapeutic strategies.

References:

1. Scott, Andrew C, Dündar, Friederike, Zumbo, Paul, Philip, Mary, Schietinger, Andrea. 2019. TOX is a critical regulator of tumour-specific T cell differentiation. In Nature, 571, 270-274. doi:10.1038/s41586-019-1324-y. https://pubmed.ncbi.nlm.nih.gov/31207604/

2. Niu, Haiyue, Wang, Huaquan. 2023. TOX regulates T lymphocytes differentiation and its function in tumor. In Frontiers in immunology, 14, 990419. doi:10.3389/fimmu.2023.990419. https://pubmed.ncbi.nlm.nih.gov/36969216/

3. Han, Jiawen, Wan, Minjie, Ma, Zhanchuan, He, Ping. . The TOX subfamily: all-round players in the immune system. In Clinical and experimental immunology, 208, 268-280. doi:10.1093/cei/uxac037. https://pubmed.ncbi.nlm.nih.gov/35485425/

4. Liang, Chaofeng, Huang, Shuxin, Zhao, Yujie, Chen, Shaohua, Li, Yangqiu. 2021. TOX as a potential target for immunotherapy in lymphocytic malignancies. In Biomarker research, 9, 20. doi:10.1186/s40364-021-00275-y. https://pubmed.ncbi.nlm.nih.gov/33743809/

5. He, Qifeng, Lu, Yijun, Tian, Wenfang, Dong, Zhongjun, Sun, Beicheng. 2022. TOX deficiency facilitates the differentiation of IL-17A-producing γδ T cells to drive autoimmune hepatitis. In Cellular & molecular immunology, 19, 1102-1116. doi:10.1038/s41423-022-00912-y. https://pubmed.ncbi.nlm.nih.gov/35986136/