α1,3 Fucosyltransferase VII Improves Intestinal Immune Homeostasis in Inflammatory Bowel Disease by Enhancing Regulatory T-Cell Intestinal Homing and Immunosuppression

Abstract

Background & aims: Regulatory T cells (Tregs) play a critical role in maintaining tissue immune homeostasis, but they are relatively insufficient at inflammatory intestinal sites in patients with inflammatory bowel disease (IBD). However, what controls Treg homing to the intestine in IBD is unknown.

Methods: α1,3 Fucosyltransferase VII (FUT7) expression in Tregs from patients with active IBD was detected by RNA sequencing. To determine whether FUT7 controls Treg intestinal homing in IBD, Treg-specific Fut7 conditional knockout (CKO) mice were constructed and used in an IBD model induced by dextran sulfate sodium. To investigate whether up-regulating FUT7 expression in Tregs plays a therapeutic role in IBD, the nanocarrier CD4-LDP-Fut7, which specifically targets Tregs to express Fut7, was constructed and used in the IBD model. In addition, whether Fut7 regulates other Treg functions was explored by mass cytometry.

Results: Compared with healthy controls, patients with active IBD had significantly decreased FUT7 expression in Tregs. In the IBD model, CKO mice had a lower frequency of colonic Tregs among CD4⁺ T cells and a lower ratio of colonic to splenic Tregs from the same mouse than their littermate controls did, indicating that Fut7 deficiency impaired the ability of Tregs to home to the intestine. Consistently, CKO mice had severe colitis, and CD4-LDP-Fut7 alleviated it in the IBD model. Mass cytometry analysis revealed that Fut7 down-regulated PD1 expression in Tregs via competition with Fut8 for the substrate GDP-fucose, thereby increasing the immunosuppressive capacity of Tregs.

Conclusions: FUT7 enhances Treg intestinal homing and immunosuppression. Thus, up-regulating FUT7 expression in Tregs could be a novel therapeutic strategy for IBD.

Keywords: FUT7; IBD; PD1; Treg.