TOX, short for thymocyte selection-associated high mobility group box protein, is a DNA-binding protein that belongs to a conserved family. It plays key roles in the development of multiple immune cell subsets, such as CD4+ T cells, innate lymphoid cells (ILCs), T follicular helper (Tfh) cells, and is crucial in CD8+ T-cell exhaustion [3]. TOX is expressed differently at all T lymphocytes development stages and its expression is driven by chronic T cell receptor stimulation and NFAT activation [1,2].

In tumor-specific T (TST) 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, they remained dysfunctional and failed to persist in tumors [1]. In the context of CAR T cells against solid tumors, CAR TILs deficient in both TOX and TOX2 were more effective than wild-type, TOX-deficient, or TOX2-deficient CAR TILs in suppressing tumor growth and prolonging survival of tumor-bearing mice, indicating TOX's role in CD8+ T cell exhaustion [4]. Also, TOX deficiency in thymocytes led to the development of fatal autoimmune hepatitis by promoting thymic IL-17A-producing γδ T-cell lineage commitment [5].

In conclusion, TOX is a critical regulator in immune cell differentiation, especially in T-cell exhaustion and activation. The use of gene knockout (KO) or conditional knockout (CKO) mouse models has revealed its significance in tumor-related T-cell dysfunction, CAR T-cell efficacy against solid tumors, and the development of autoimmune hepatitis, providing potential therapeutic targets for cancer and autoimmune diseases.

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. Seo, Hyungseok, Chen, Joyce, González-Avalos, Edahí, Bhandoola, Avinash, Rao, Anjana. 2019. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. In Proceedings of the National Academy of Sciences of the United States of America, 116, 12410-12415. doi:10.1073/pnas.1905675116. https://pubmed.ncbi.nlm.nih.gov/31152140/

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/