Abstract
To maintain immunological homeostasis, the intestinal immune system is equipped with unique innate and acquired immunocompetent cells operated by crosstalk between the host and environmental factors such as nutrition and intestinal microbiota. A lipid mediator, sphingosine 1-phosphate (S1P), has recently been identified as a functional molecule in the regulation of lymphocyte trafficking, especially at the step of emigration from secondary lymphoid organs. Our recent findings revealed that S1P uniquely regulates the innate and acquired phase of intestinal immunity. When the S1P-mediated pathway was disrupted, the trafficking of both peritoneal B1 and Peyer's patch B2 cells into the intestine was inhibited, leading to impaired intestinal IgA responses to T-independent and -dependent antigens. In contrast, intraepithelial T lymphocytes (IELs), unique lymphocytes observed in the intestinal epithelium, showed a distinct dependence upon S1P. Conventional single-positive thymocytes use S1P for their trafficking into the intestine, where they differentiate to CD4 or CD8αβ IELs expressing TCRαβ. However, S1P did not play a role in the trafficking of unconventional thymic precursors of CD8αα IELs. In addition, we found that S1P contributed to the development of allergic diarrhea, particularly in the trafficking of pathogenic T and mast cells into the large intestine. These findings collectively suggest that S1P plays a pivotal role in the regulation of both immunosurveillance and immunological homeostasis in the intestine. The fact that lipids are abundantly provided by intestinal microbiota and nutrition raises the possibility that these environmental factors may uniquely participate in the regulation of intestinal immunity through lipid mediators such as S1P.
