Discussion
Our data demonstrated that Fut1 KO splenocytes exhibited distinct transcriptome profiles from WT splenocytes, with Thbs1 showing the most significant down-regulation in Fut1 KO splenocytes. Since THBS1 was effective in inhibiting CD4 T cell proliferation and Th1/Th17 differentiation, Fut1 KO splenocytes more significantly enhanced the proliferation of CD4 T cells and the differentiation into Th1/Th17 subsets compared to WT splenocytes.
Previous studies have investigated the effects of fucosylation on immune cells. For instance, T cells treated with the pan-fucosylation inhibitor 2-deoxy-2-fluorofucose (2FF) were shown to be more easily activated by peptide-major histocompatibility complex (MHC) (14), while treatment with the terminal FUT1/2 inhibitor, 2-deoxy-D-galactose (2-D-gal), promoted Th17 cell differentiation (1). Also, 2FF was reported to upregulate MHC class II, CD83, CD86 and CD40 on dendritic cells (DCs) (14). Moreover, the overexpression of type I Lewis antigens, which are terminal fucosylated carbohydrate epitopes, in colon cancer cells induced an immunosuppressive phenotype in DCs (15). In contrast, it was reported that 2-D-gal suppressed the expression of MHC class II and CD86 on macrophages and disrupted the interaction between antigen-presenting cells (APCs) and T cells (2). In addition to these previous findings, our study showed that deficiency in FUT1-mediated terminal fucosylation in splenocytes potentiated the stimulating effects of splenocytes as APCs on CD4 T cell proliferation and Th1/Th17 differentiation due to the reduced expression of THBS1. Further studies are needed to identify the specific cell types within splenocytes that exhibit altered THBS1 production in response to FUT1 deficiency, and to investigate the underlying molecular pathways through which FUT1-mediated fucosylation regulates THBS1 expression in these cells.
THBS1 is a matricellular glycoprotein that plays crucial roles in angiogenesis, cancer and inflammation. It is secreted by diverse cell types, including endothelial cells, fibroblasts, adipocytes, smooth muscle cells and APCs, reflecting the involvement of THBS1 in regulating multiple cellular processes associated with tissue repair and inflammation resolution (16,17). While THBS-1 has long been investigated in the context of vascular health and disease, recent research has shed light on its emerging role in the immune response. Especially, THBS1 derived from APCs was reported to suppress the capacity of APCs to allosensitize CD4 T cells, promoting the survival of corneal allografts (18). It was also observed that THBS1 expression by APCs was necessary for TGF-β2-expressing APCs to induce Foxp3+ Tregs (19). Furthermore, exogenous THBS1 was found to inhibit the differentiation of CD4 T cells into Th17 cells and stimulate their differentiation towards Tregs (20), confirming the role of THBS1 as a negative regulator of pro-inflammatory T cell activation. Consistent with these findings, in our study, THBS1 significantly abrogated the effects of Fut1 KO splenocytes on the induction of CD4 T cell proliferation and Th1/Th17 differentiation, although it did not affect Treg differentiation.
In conclusion, we herein demonstrate that Fut1 deficiency in splenocytes leads to reduced THBS1 secretion, thereby promoting CD4 T cell proliferation and driving Th1/Th17 differentiation. These findings contribute to our understanding of the interplay between splenocyte fucosylation, THBS1 expression and T cell responses. Future strategies aimed at modulating fucosylation in APCs to upregulate THBS1 expression may hold promise as potential therapeutic approaches for the management of T-cell-mediated immune disorders.