TOX, short for thymocyte selection-associated high mobility group box protein, is a DNA-binding protein belonging to a conserved family. It plays key roles in the development of various immune cell subsets such as CD4+ T cells, innate lymphoid cells (ILCs), T follicular helper (Tfh) cells, and is involved in CD8+ T-cell exhaustion [2]. TOX contains a DNA-binding domain, regulating transcription by modifying chromatin structure and multi-protein complex formation [4].

Deletion of Tox in tumour-specific T (TST) cells in tumours abrogated the exhaustion program, as Tox-deleted TST cells did not upregulate genes for inhibitory receptors, yet remained dysfunctional and failed to persist in tumours. This suggests that TOX-induced exhaustion program may prevent overstimulation of T cells and activation-induced cell death in cancer [1]. In another study, TOX-deficient mice had promoted thymic IL-17A-producing γδ T-cell lineage commitment, leading to the development of fatal autoimmune hepatitis. Transfer of γδ T cells from these mice reproduced AIH, indicating TOX's role in autoimmune control [3].

In conclusion, TOX is crucial in regulating the differentiation and function of T lymphocytes. Gene knockout mouse models have revealed its significance in cancer and autoimmune diseases, providing insights into its underlying mechanisms and potential as a therapeutic target in these disease areas.