2-D-gal Targets Terminal Fucosylation to Inhibit T-cell Response in a Mouse Skin Transplant Model

Abstract

Background. Organ allograft rejection is mainly driven by T-cell response. Studies have shown that fucosylation plays essential roles in the immune cell development and function. Terminal fucosylation inhibitor, 2-deoxy-D-galactose (2-D-gal), has been reported to suppress immunoresponse of macrophages, but its effects on T-cell–mediated immune response and transplant rejection have not been fully explored. Methods. The terminal fucosylation level in T cells was detected through ulex europaeus agglutinin-I staining. The consequences of 2-D-gal on murine T-cell proliferation, activation, cytokine secretion, and cell cycle were investigated in vitro. T-cell receptor signaling cascades were examined. Last, mouse skin transplant model was utilized to evaluate the regulatory effects of 2-D-gal on T-cell response in vivo. Results. The expression of fucosyltransferase1 was upregulated in CD3/CD28-activated T cells along with an elevation of α(1,2)-fucosylation level as seen by ulex europaeus agglutinin-I staining. Furthermore, 2-D-gal suppressed T-cell activation and proliferation, decrease cytokines production, arrest cell cycle, and prevent the activation of T-cell receptor signaling cascades. In vivo experiments showed that 2-D-gal limited T-cell proliferation to prolong skin allograft in mice. This was accompanied by lower level of inflammatory cytokines, and were comparable to those treated with Cyclosporin A. Conclusions. Terminal fucosylation appears to play a role in T-cell activation and proliferation, and its inhibitor, 2-D-gal, can suppress T-cell activation and proliferation both in vitro and in vivo. In a therapeutic context, inhibiting terminal fucosylation may be a potential strategy to prevent allogeneic transplant rejection.

Identification of glycosyltransferase genes for diagnosing T-cell mediated rejection and predicting graft loss in kidney transplantation

“…By evaluating molecular changes in tissue that precede morphological changes, a new diagnostic method could overcome the limitations of current histopathological diagnosis. A growing body of literature suggests that abnormal changes in glycans are associated with the T cell immune response during graft rejection [20,21,34]. Based on this, we obtained renal graft rejection-related microarray expression data from GEO and explored the role of GTGs in renal graft rejection at a molecular level.…”

“…Accumulating evidence indicates that glycan changes play a crucial role in T-cell-mediated immune response during graft rejection. Our previous study showed that terminal fucosylation is crucial for T-cell activation and proliferation, suggesting that inhibiting terminal fucosylation may be a viable strategy to prevent allogeneic transplant rejection [20]. In parallel, deletion of fucosyltransferase-VII (FucT-VII) impairs leukocyte recruitment and induces T-cell exhaustion, preventing chronic graft vasculopathy and rejection [21].…”