TOX
Description
The TOX (thymocyte selection associated high mobility group box) is a protein-coding gene located on chromosome 8.
Thymocyte selection-associated high mobility group box protein TOX is a protein that in humans is encoded by the TOX gene. TOX drives T-cell exhaustion and plays a role in innate lymphoid cell development. The TOX gene encodes a protein that belongs to a large superfamily of chromatin associated proteins that share an approximately 75 amino acid DNA binding motif, the HMG (high mobility group)-box. Some high mobility group (HMG) box proteins contain a single HMG box motif and bind DNA in a sequence-specific manner, while other members of this family have multiple HMG boxes and bind DNA in a sequence-independent but structure-dependent manner. While TOX has a single HMG-box motif, it is predicted to bind DNA in a sequence-independent manner. TOX is a member of a small subfamily of proteins (TOX2, TOX3, and TOX4) that share almost identical HMG-box sequences. TOX2 has been identified to play a role in the differentiation of T follicular helper cell. TOX2 is thought to be a downstream signal of BCL-6. TOX3 has been identified as a breast cancer susceptibility locus. TOX is highly expressed in the thymus, the site of development of T lymphocytes.
TOX is a transcription regulator involved in the commitment and development of neural stem cells and cortical development, as well as in lymphoid cell development and the formation of secondary lymphoid tissues. It binds to GC-rich DNA sequences and can modify chromatin structure, influencing the accessibility of transcription factors. During cortical development, TOX regulates the neural stem cell pool, preventing premature differentiation, and promotes neurite outgrowth in newborn neurons. It may activate or repress genes crucial for neural stem cell fate, including SOX2, EOMES, and ROBO2. TOX is essential for the development of lymphoid tissue inducer (LTi) cells, which are critical for the formation of lymph nodes and Peyer's patches. It acts as a checkpoint during thymocyte selection, promoting T cell lineage commitment. TOX is required for the development of various T cell subsets, including CD4+ helper T cells, CD8+ cytotoxic T cells, regulatory T cells, and CD1D-dependent natural killer T (NKT) cells. It is also involved in the differentiation of common lymphoid progenitors (CMP) into innate lymphoid cells (ILC) and may regulate the NOTCH-mediated gene program during ILC differentiation. TOX is required for NK cell lineage commitment during the progenitor phase of NK cell development in the bone marrow. Upon chronic antigen stimulation, TOX promotes the generation of exhausted T cells, suppressing effector and memory T cell programming. It may regulate the expression of genes encoding inhibitory receptors like PDCD1, contributing to the exhaustion program and preventing T cell overstimulation and activation-induced cell death.
TOX is also known as TOX1.
