N-Glycan Branching Decouples B Cell Innate and Adaptive Immunity to Control Inflammatory Demyelination

Abstract

Summary B cell depletion potently reduces episodes of inflammatory demyelination in multiple sclerosis (MS), predominantly through loss of innate rather than adaptive immunity. However, molecular mechanisms controlling innate versus adaptive B cell function are poorly understood. N -glycan branching, via interactions with galectins, controls endocytosis and signaling of cell surface receptors to control cell function. Here we report that N -glycan branching in B cells dose dependently reduces pro-inflammatory innate responses by titrating decreases in Toll-like receptor-4 (TLR4) and TLR2 surface expression via endocytosis. In contrast, a minimal level of N -glycan branching maximizes surface retention of the B cell receptor (BCR) and the CD19 co-receptor to promote adaptive immunity. Branched N -glycans inhibit antigen presentation by B cells to reduce T helper cell-17 (T H 17)/T H 1 differentiation and inflammatory demyelination in mice. Thus, N -glycan branching negatively regulates B cell innate function while promoting/maintaining adaptive immunity via BCR, providing an attractive therapeutic target for MS.

Galectin-9 regulates the threshold of B cell activation and autoimmunity

“…However, the specific glycosylation sites and structural constraints of these interactions remain to be fully resolved. Branching of N-glycans has been shown to regulate aspects of B cell activation with respect to TLR-induced B cell functional responses ( Mortales et al, 2020 ). Branched complex N-glycans serve as a ligand for galectins, including Gal9.…”

N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation

“…GlcNAc and/or N-glycan branching also play important roles in suppressing T cell and B cell mediated inflammatory demyelination (17,28,(30)(31)(32)(33)35,37,38). .…”

“…GlcNAc and/or N -glycan branching also play important roles in suppressing T cell– and B cell–mediated inflammatory demyelination ( 17 , 28 , 30 – 33 , 35 , 37 , 38 ). In T cells, GlcNAc and N -glycan branching suppress activation signaling via the T-cell receptor ( 17 , 21 , 22 ), inhibit pro-inflammatory T H 1 and T H 17 differentiation ( 24 , 38 ), and enhance anti-inflammatory T regulatory cell differentiation ( 24 ).…”

“…B-cell depletion is a potent therapy in MS, predominantly acting by suppressing innate antigen presenting cell function rather than via antibody production ( 61 , 62 ). N-glycan branching in B cells reduces pro-inflammatory innate signaling via toll-like receptors and inhibits antigen presenting cell activity, yet it promotes adaptive responses through the B-cell receptor ( 28 ). Thus, oral GlcNAc is uniquely positioned as a therapeutic to reverse three major targets driving MS pathogenesis, namely pro-inflammatory T-cell responses, pro-inflammatory innate B-cell activity, and myelin repair.…”

“…Poly-valent galectinglycoprotein interactions at the cell surface form a macromolecular lattice that simultaneously controls the movement, clustering and/or endocytosis of multiple receptors and transporters to control signaling, cell growth, differentiation and death (17)(18)(19)(20)(21)(22)(23)(24). For example, N-glycan branching controls epithelial cell growth by regulating receptor tyrosine kinases endocytosis (17)(18)(19)(20), promotes glucose uptake in mesenchymal and pancreatic b cells by inhibiting glucose transporter endocytosis (19,25) and reduces T cells, B cell and neutrophil pro-inflammatory responses by co-regulating the clustering and/or endocytosis of multiple glycoproteins (17,23,(26)(27)(28)(29). These mechanisms in turn impact cancer, type II diabetes and autoimmunity (20).…”