Core Fucosylation of the T Cell Receptor Is Required for T Cell Activation

Abstract

CD4+ T cell activation promotes the pathogenic process of systemic lupus erythematosus (SLE). T cell receptor (TCR) complex are highly core fucosylated glycoproteins, which play important roles in T cell activation. In this study, we found that the core fucosylation of CD4+ T cells was significantly increased in SLE patients. Loss of core fucosyltransferase (Fut8), the sole enzyme for catalyzing the core fucosylation of N-glycan, significantly reduced CD4+ T cell activation and ameliorated the experimental autoimmune encephalomyelitis-induced syndrome in Fut8−/− mice. T cell activation with OVA323–339 loaded major histocompatibility complex II (pMHC-II) on B cell was dramatically attenuated in Fut8−/−OT-II CD4+ T cells compared with Fut8+/+OT-II CD4+ T cells. Moreover, the phosphorylation of ZAP-70 was significantly reduced in Fut8+/+OT-II CD4+ T cells by the treatment of fucosidase. Our results suggest that core fucosylation is required for efficient TCR–pMHC-II contacts in CD4+ T cell activation, and hyper core fucosylation may serve as a potential novel biomarker in the sera from SLE patients.

CDG and immune response: From bedside to bench and back

“…In the cancer microenvironment, blocking core‐fucosylation induces a T cell response. In contrast, in colitis and systemic lupus erythematosus increased core‐fucosylation is accompanied by an increased T cell activation and response . However, in both cases, core‐fucosylation inactivation may be a potential new therapeutic avenue.…”

“…Since TGF‐β1 supplementation in Fut8 deficient mice rescued the emphysema‐like phenotype, it suggests supplementation with this cytokine as a potential treatment for patients. Remarkably, in vitro and in vivo studies, have shown that FUT8 depletion has a greater and more generalized impact on the immune system components and response . Fut8 −/− mice exhibited an imbalanced immune cell count with high levels of eosinophils and monocytes, as well as an affected response to bacterial lipopolysaccharide (LPS) stimulation with decreased IFN‐β production .…”

“…B cell anomalies include: lymphopenia, hypogammaglobulinemia, impaired pre‐ and IgG‐BCR antigen recognition, assembly and lipid raft association . Concomitantly, Fut8 defective mice showed inefficient immunization . Furthermore, a genome wide association study has unraveled FUT8 as a gene of interest in IgG glycosylation, indicating that FUT8 might also have a direct impact on antibody function .…”

“…Furthermore, a genome wide association study has unraveled FUT8 as a gene of interest in IgG glycosylation, indicating that FUT8 might also have a direct impact on antibody function . T cell abnormalities comprise: failure to transport TCRs to membrane lipid rafts, reduced CD4 + T cell activation, lower production of Th1 and Th2 cytokines with concomitant decrease of the T cell regulatory protein Foxp3 . Thus, FUT8 impairs the communication between B and T cells, being a crucial player across all immune mechanisms both in vitro and in vivo …”

Structural basis of substrate recognition and catalysis by fucosyltransferase 8

“…This modification, referred to as core-fucosylation, is ubiquitous throughout mammalian tissues and represents an important step in the maturation of complex N-glycans within the Golgi apparatus. Core fucosylation modulates the activity of many cell surface receptors, including: TGFβ1R 1, 2 , EGFR 3 , BCR 4 , TCR 5, 6 , CD14-mediated TLR2/4 signalling 7, 8 , and PD-1 9 . It also modulates the affinity of ligands for their receptors, the most notable example being the role that core fucose plays in decreasing the affinity of immunoglobulin G (IgG) for FcγRIIIa 10, 11 .…”