Tnfrsf4, also known as OX40 (CD134), is a member of the tumour necrosis factor receptor family and functions as a T cell co-stimulatory molecule [1]. It is activated by its cognate ligand OX40L (CD134L, CD252). The OX40-OX40L interactions are involved in promoting T cell survival, effector T cell phenotype, T cell memory, reducing regulatory function, increasing effector cytokine production and enhancing cell mobility. This pathway is significant in immune-related biological processes and has potential implications in autoimmunity [1].

In various diseases, Tnfrsf4 shows distinct impacts. In chronic myeloid leukemia, Tregs expressing Tnfrsf4 protect leukemia stem cells from CD8+ CTL-mediated elimination, and targeting TNFRSF4 signaling can reduce Tregs' protective function towards leukemia stem cells [2]. In hepatocellular carcinoma, elevated TNFRSF4 expression affects immune cell infiltration, gene mutation, and is an independent prognostic marker [3]. In non-M3 acute myeloid leukemia, elevated TNFRSF4 expression is associated with poor prognosis, as well as mutations in genes like TP53, FLT3, and NPM1 [4]. In endometrial carcinoma, TNFRSF4 is positively correlated with tumor-infiltrating immune cells (such as CD4+ T cells, CD8+ T cells, and Tregs) and is related to patient prognosis, thus serving as a potential biomarker for prognosis prediction and immunomodulation [5].

In conclusion, Tnfrsf4, as a key T cell co-stimulatory molecule, plays an important role in immune-related biological processes. Studies, especially those on its expression in different cancer types, have revealed its significance in disease prognosis, immune cell infiltration, and immune-mediated tumor protection. Understanding Tnfrsf4 function through in vivo studies may provide new insights into disease mechanisms and potential therapeutic targets.

References:

1. Webb, Gwilym J, Hirschfield, Gideon M, Lane, Peter J L. . OX40, OX40L and Autoimmunity: a Comprehensive Review. In Clinical reviews in allergy & immunology, 50, 312-32. doi:10.1007/s12016-015-8498-3. https://pubmed.ncbi.nlm.nih.gov/26215166/

2. Hinterbrandner, Magdalena, Rubino, Viviana, Stoll, Carina, Ochsenbein, Adrian F, Riether, Carsten. 2021. Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells. In JCI insight, 6, . doi:10.1172/jci.insight.151797. https://pubmed.ncbi.nlm.nih.gov/34727093/

3. Wang, Di, Hu, Huan, Ding, Huan, Tian, Feifei, Chi, Qingjia. . Elevated expression of TNFRSF4 impacts immune cell infiltration and gene mutation in hepatocellular carcinoma. In Cancer biomarkers : section A of Disease markers, 36, 147-159. doi:10.3233/CBM-210538. https://pubmed.ncbi.nlm.nih.gov/36591653/

4. Gu, Siyu, Zi, Jie, Han, Qi, Song, Chunhua, Ge, Zheng. 2020. Elevated TNFRSF4 gene expression is a predictor of poor prognosis in non-M3 acute myeloid leukemia. In Cancer cell international, 20, 146. doi:10.1186/s12935-020-01213-y. https://pubmed.ncbi.nlm.nih.gov/32390761/

5. Ma, Heng, Feng, Peng-Hui, Yu, Shuang-Ni, Yu, Qi, Chen, Jie. 2022. Identification and validation of TNFRSF4 as a high-profile biomarker for prognosis and immunomodulation in endometrial carcinoma. In BMC cancer, 22, 543. doi:10.1186/s12885-022-09654-6. https://pubmed.ncbi.nlm.nih.gov/35562682/