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.