Regulation Of T Cell Proliferation And Activation By Terminal Fucosylation Inhibitor And Its Effect On Mouse Skin Transplantation

Fucosylation is an important post-translational modification that is closely related to the development and function of immune cells.Fucosyltransferases are involved in the synthesis of fucose-containing polysaccharides,i.e.fucosyltransferases(FUTs)are used to connect fucosyltransferases to fucosyltransferases(FUTs).So far,a total of 13 FUTs have been discovered.Fucosylation can be divided into α(1,2)-,α(1,3/4)-,α(1,6)and o-fucosylation reactions.Among them,α(1,2)-and α(1,3/4)-FUTs catalyze the terminal or subterminal fucosylation of the acceptor molecule,while α(1,6)-FUT catalyze the core fucosylation of the innermost layer of N-glycan.O-Fucosylation is catalyzed by POFUT1/2 to directly link fucose to serine and threonine residues in epidermal growth factor(EGF)-like domains or thrombospondin type 1 repeat domains.Fucosylation plays an important role in the development and function regulation of immune cells.Studies have shown that core fucosylation participates in TCR signal transduction and T cell activation and proliferation.In recent years,it has been reported that terminal fucosylation can be used as a marker of M1 macrophages.However,whether terminal fucosylation is also involved in T cell immune response has not been reported.In this study,we found that when T cells were activated,the expression of terminal fucosylation level increased,while T cells treated with 2-D-Gal,a terminal fucosylation inhibitor,inhibited T cell proliferation in a dose-dependent manner.2-D-gal significantly inhibited the expression of T cell activation markers(CD69,CD25,CD44,and CD71)and Thl and Th2 cytokines(IL-2,IFN-γ,TNF-α,and IL-4).At the same time,we found that 2-D-Gal can block the T cell cycle in the G0/G1 phase and inhibit the activation of proximal and distal TCR signaling pathways(ZAP70,LCK,LAT,MAPK and NF-KB).T cells treated with 2-D-Gal were in a state of low response,and their il-2 secretion was inhibited.Adding IL-2 could rescue the inhibitory effect of 2D-Gal on T cells.When T cells were treated with 2-D-Gal,increased cytoplasmic calcium concentration and nuclear translocation of activated T nuclear factor(NFAT)was inhibited during T cell activation.In addition,we evaluated the effect of 2-D-Gal on allograft rejection in a mouse allograft model.Compared with mice in Allogeneic group,2-D-Gal treatment can prolong the survival time of skin transplantation,and the proliferation of T cells and secretion of inflammatory cytokines in mice are inhibited.In summary,our results suggest that 2-D-Gal,a terminal fucosylation inhibitor,may inhibit T cell proliferation,activation and secretion of related cytokines by inhibiting the activation of proximal and distal TCR signaling pathways.It is suggested that terminal fucosylation inhibitor 2-D-Gal May prolong the survival time of skin grafts by regulating the immune function of T cells.This study not only provides experimental basis for studying the relationship between fucosylation and immune response,but also provides experimental basis for the potential application of terminal fucosylation inhibitor 2-D-Gal in organ transplant rejection.