S1pr1 (sphingosine-1-phosphate receptor 1) is a Gi-coupled receptor expressed on the surface of lymphocytes. When it recognizes high levels of ligand (S1P) in the blood and lymph, egress of the cells from lymphoid organs into the blood is promoted. Downregulation or desensitization of this receptor enables lymphocytes to subsequently migrate from the blood into tissues.
The last 12 amino acids of the encoded protein carry a motif that is important for receptor desensitization following exposure to ligand. These mice carry a Thr-Ser-Ser (TSS) to Ala-Ala-Ala (AAA) mutation in this region that leads to a loss in sensitivity for ligand-mediated receptor down-modulation, leading to partial block in the desensitization process.
Mice are resistant to S1P-mediated S1PR1 internalization in naive T cells, follicular B cells and marginal zone (MZ) B cells. Augmented responses to S1P in chemotaxis assays and higher S1PR1 expression on MZ B cells are also seen. In addition, MZ B cells in mutant mice show abnormal distribution; they are confined to the marginal zone compartment and absent from the follicles. Mutant mice have normal numbers of naive T cells, follicular B cells and MZ B cells. Heterozygous and homozygous mutant mice show essentially the same phenotype.
