S1pr5, short for sphingosine 1-phosphate receptor 5, is one of the five subtypes of the G-protein-coupled sphingosine 1-phosphate receptor (S1PR). S1PRs are involved in regulating the trafficking of neutrophils, lymphocytes, tumor cells, etc., and have significant impacts on the immune system, as well as lung and liver tissues. S1pr5 is associated with pathways that govern cell migration and tissue-resident lymphocyte development [2].

In a murine allogeneic haematopoietic stem cell transplantation model, S1pr5 deficiency in NK cells blocked their migration from the bone marrow to GVHD target organs, aggravating GVHD, while not interfering with the antitumour effects of NK and T cells in vivo, indicating its role in balancing GVHD and graft-versus-tumour (GVT) activity [5]. In another study, S1pr5 was found to powerfully impair tissue-resident memory T cell (TRM) formation, and tissue-derived TGF-β limits S1pr5 expression by infiltrating T cells. Ectopic expression of S1pr5 selectively impaired TRM cell development, while loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. This identified the T-bet-ZEB2-S1PR5 axis as a mechanism modulating the generation of tissue-resident lymphocytes [1,3]. Additionally, in fasting-related studies, the redistribution of NK cells to the bone marrow during fasting required S1pr5 and CXCR4, which was related to improved NK cell-mediated anti-tumour immunity [4].

In conclusion, S1pr5 is crucial in regulating the trafficking and retention of immune cells, such as NK cells and T cells. Model-based research, especially using gene knockout in mouse models, has revealed its significant roles in diseases like graft-versus-host disease, in modulating tissue-resident lymphocyte formation, and in the context of fasting-related anti-tumour immunity. These findings contribute to understanding immune-related disease mechanisms and potentially developing new therapeutic strategies.

References:

1. Hallisey, Victoria M, Schwab, Susan R. 2021. Blood-thirsty: S1PR5 and TRM. In The Journal of experimental medicine, 219, . doi:10.1084/jem.20211971. https://pubmed.ncbi.nlm.nih.gov/34714328/

2. Chen, Hongyu, Wang, Junmin, Zhang, Caiyun, Ji, Guang, Wu, Tao. 2022. Sphingosine 1-phosphate receptor, a new therapeutic direction in different diseases. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 153, 113341. doi:10.1016/j.biopha.2022.113341. https://pubmed.ncbi.nlm.nih.gov/35785704/

3. Evrard, Maximilien, Wynne-Jones, Erica, Peng, Changwei, Jameson, Stephen C, Mackay, Laura K. 2021. Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes. In The Journal of experimental medicine, 219, . doi:10.1084/jem.20210116. https://pubmed.ncbi.nlm.nih.gov/34677611/

4. Delconte, Rebecca B, Owyong, Mark, Santosa, Endi K, Merad, Miriam, Sun, Joseph C. 2024. Fasting reshapes tissue-specific niches to improve NK cell-mediated anti-tumor immunity. In Immunity, 57, 1923-1938.e7. doi:10.1016/j.immuni.2024.05.021. https://pubmed.ncbi.nlm.nih.gov/38878769/

5. Wang, Feiyan, Zhao, Shasha, Gu, Zhenyang, Wang, Lili, Gao, Chunji. 2019. S1PR5 regulates NK cell responses in preventing graft-versus-host disease while preserving graft-versus-tumour activity in a murine allogeneic haematopoietic stem cell transplantation model. In Hematological oncology, 38, 89-102. doi:10.1002/hon.2669. https://pubmed.ncbi.nlm.nih.gov/31465552/