CXCR6, a G protein-coupled receptor with 7 transmembrane domains, is the receptor for the chemokine CXCL16, which exists in membrane or soluble form. It plays a crucial role in immunosurveillance as a marker for resident memory T (TRM) cells, enabling their interaction with epithelial cells. The CXCR6/CXCL16 axis is involved in various biological processes, such as immune cell migration and intercellular communication [1,3,6]. Genetic models, like KO mouse models, are valuable for studying CXCR6's functions.

In cancer, mice deficient in Cxcr6 or with blocked CXCR6-ligand interaction experience poorer control of tumor proliferation by CD8+ T cells and NKT cells, especially in the liver [1]. In Alzheimer's disease, Cxcr6 deficiency impairs the accumulation, tissue residency programming, and clonal expansion of brain PD-1+CD8+ T cells, ultimately increasing pro-inflammatory cytokine production from microglia [2]. In NASH, auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology, and in renal fibrosis, CXCR6+ ILC3s migrate from the intestine to the kidney and exacerbate the condition [4,5].

In conclusion, CXCR6 is essential for functions related to immune cell-mediated immunosurveillance, cell-cell communication, and tissue homeostasis. Model-based research, especially using Cxcr6 KO mouse models, has revealed its significance in diseases such as cancer, Alzheimer's disease, NASH, and renal fibrosis, highlighting its potential as a therapeutic target or biomarker in these disease areas.

References:

1. Mabrouk, Nesrine, Tran, Thi, Sam, Ikuan, Fabre, Elizabeth, Tartour, Eric. 2022. CXCR6 expressing T cells: Functions and role in the control of tumors. In Frontiers in immunology, 13, 1022136. doi:10.3389/fimmu.2022.1022136. https://pubmed.ncbi.nlm.nih.gov/36311728/

2. Su, Wei, Saravia, Jordy, Risch, Isabel, Peng, Junmin, Chi, Hongbo. 2023. CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology. In Nature immunology, 24, 1735-1747. doi:10.1038/s41590-023-01604-z. https://pubmed.ncbi.nlm.nih.gov/37679549/

3. Bao, Nandi, Fu, Bo, Zhong, Xiaoling, Xu, Shiping, Li, Tingting. 2023. Role of the CXCR6/CXCL16 axis in autoimmune diseases. In International immunopharmacology, 121, 110530. doi:10.1016/j.intimp.2023.110530. https://pubmed.ncbi.nlm.nih.gov/37348231/

4. Liang, Zhou, Tang, Ziwen, Zhu, Changjian, Chen, Wei, Zhou, Yi. 2024. Intestinal CXCR6+ ILC3s migrate to the kidney and exacerbate renal fibrosis via IL-23 receptor signaling enhanced by PD-1 expression. In Immunity, 57, 1306-1323.e8. doi:10.1016/j.immuni.2024.05.004. https://pubmed.ncbi.nlm.nih.gov/38815582/

5. Dudek, Michael, Pfister, Dominik, Donakonda, Sainitin, Heikenwälder, Mathias, Knolle, Percy A. 2021. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. In Nature, 592, 444-449. doi:10.1038/s41586-021-03233-8. https://pubmed.ncbi.nlm.nih.gov/33762736/

6. Wang, Fang-Tao, Wu, Tian-Qi, Lin, Yin, Yin, Lu, Chen, Chun-Qiu. 2024. The role of the CXCR6/CXCL16 axis in the pathogenesis of fibrotic disease. In International immunopharmacology, 132, 112015. doi:10.1016/j.intimp.2024.112015. https://pubmed.ncbi.nlm.nih.gov/38608478/