Pyruvate enhances oral tolerance via GPR31

概要

[目的(Purpose)]
CX3CRihigh myeloid cells in the small intestine mediate the induction of oral tolerance by driving regulatory T (Treg) cells. GPR31.is reported to be selectively expressed on CX3CR1high myeloid cells of Payer' s patches and small intestinal lamina propria. Bacterial metabolites, e.g., pyruvate and lactate, induce a dendrite extension of CX3CRihigh myeloid cells into the intestinal lumen via GPR31. Here, we aim to identify whether pyruvate-GPR31 axis is involved in the induction of oral tolerance.

[方法ならびに成績(Methods/Results)]
To evaluate the induction of oral tolerance, we performed the delayed type hypersensitivity (DTH) model on mice. In ovalbumin (OVA) -fed Gor31-deficient mice, an OVA-induced delayed-type hypersensitivity response was substantially induced, demonstrating the defective induction of oral tolerance in Gpr31-deficient mice. By analyzing the population of immune cells in the small intestinal lamina propria, we found that the percentage of ROR y t* Treg cells in the small intestine was reduced in Gpr31-deficient mice. We also found the percentage of antigen-specific ROR y t* Treg cells was significantly lower in Gpr31-deficient mice compared to the wild-type mice through the OT-II transfer experiment.

In pyruvate-treated wild-type mice, a low dose of OVA efficiently induced oral tolerance. IL-10 production from intestinal CX3CRIngh myeloid cells was increased by OVA ingestion in wild™type mice, but not in Gpr31-deficient mice. CX3CRihigh myeloid cell-specific IL-10-deficient mice showed a defective induction of oral tolerance to OVA and a decreased accumulation of OVA-specific Tre cells in the small intestine.

[総括 (Conclusion)]
These findings demonstrate that pyruvate acts on small intestinal CX3CRIhigh myeloid cells via GPR31 and mediates the maintenance of intestinal Treg cells through the production of IL-10, thereby contributing to the effective induction of oral tolerance