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Glycans and B-cells: How glycans influence adaptive immunity

The body’s autoimmune response has been leveraged by cancer researchers to propel immunotherapy tools into clinical use. Although the main focus has been on the ability of T-cells to fight cancer cells, the involvement of tumor-infiltrating B-cells is also becoming evident. Tumor-infiltrating B lymphocytes (TIL-Bs) are produced in much higher amounts in various cancers than in healthy tissues, which highlights their positive prognostic value (1). However, their exact role in cancer remains controversial, with the demonstration of both positive and negative impacts.


While they play a critical role in the recruitment of other immune cells and the production of tertiary lymphoid structures to enhance antitumor immunity, some B-cell types have also been shown to promote inflammation and suppress the immune response (2). The conflicting evidence of TIL-B action in cancer points to the need to better understand how B-cells develop and interact with their targets. 

One way B-cells promote immune response is through the production of antibodies for antigen recognition. It is interesting to note that many of these glycoantigens, such as MUC1 (3) and ganglioside D3 (4), are aberrantly glycosylated in cancer. That’s why investigating their interactions with glycans can enlighten us about the role of glycosylation in the development, differentiation, maturation, and survival of B-cells. 

B-cell development 

Germinal center (GC) B-cell development and differentiation are prerequisites for adaptive immune response through B-cell-mediated antibody production. Initially, naive B-cells found in the spleen, tonsil, and primary lymph nodes are exposed to the antigens on the surface of dendritic cells, which leads to their activation.

Activated B-cells form clusters of germinal centers in primary follicles, where they proliferate, mature, and differentiate. More specifically, they undergo a process called somatic hypermutation, defined as the introduction of random mutations to the B-cell receptor regions. Thus, the body generates a library of B-cells with highly diverse receptors with an affinity to various antigens.

These B-cells are filtered according to their interactions with the antigens displayed on the surface of follicular dendritic cells. Depending on the antigens presented, the B-cells undergo class switch recombination to differentiate into plasma cells or memory B-cells, which are responsible for the secretion of antibodies in the bloodstream. 

As we zoom into each step of this process, we encounter glycan-lectin interactions that promote or regulate B-cell development at various points. 

Galectins modulate B-cell development 

Recent studies uncovered the role of galectins in regulating the adaptive immune response. It was shown that galectins can interact with the surface glycans of both innate and adaptive immune cells. Galectin interactions play a multifaceted role in modulating B-cell activation and germinal center-type differentiation essential for maintaining immune response (5).    

Gal-1 was implicated as a promoter of B-cell receptor-mediated signaling, which increased B-cell activation and proliferation (6). On the other hand, Gal-1 was also shown to interact with immune receptors, such as CD45—which is involved in B-cell activation and survival, to modulate activation (7). Similarly, Gal-3 and Gal-9 reduced activation and GC development rates in splenic and tonsillar B-cells, respectively (8–9) 

Furthermore, Galectins are one of the key players in the differentiation fate of B-cells. For example, Gal-1 and Gal-8 can be effective promoters of B-cell differentiation, driving the early stages of immunoglobulin production (10) or establishing plasma cell homeostasis (11). In other studies, Gal-1 was shown to induce apoptosis in active B-cells to terminate immune response (12).

Further research also revealed that the modulatory activity of galectins was dependent on the surface glycan profiles of B-cells. For example, Giovannone et al. demonstrated the role of the B-cell N-glycan composition on Gal-9.

Although Gal-9 strongly bound naive memory B-cells to blunt their activity and exhibited strong binding, GC B-cells exhibited diminished Gal-9 binding due to the I-branching of their surface glycoproteins (9). Thus, a bidirectional relationship between the glycan profiles of B-cells and the level of suppression through galectin binding becomes clear.  

O-linked glycans and B-cell differentiation 

The dynamic nature of GC B-cell glycan profiles was further investigated to uncover the role of glycan remodeling in B-cell differentiation.  

O-glycan modifications were previously identified in T cells, where altered T-antigen expression on the CD8 glycoprotein was associated with changes in T-cell activity. The T-antigen levels of T cells at different maturity levels were detected by peanut agglutinin (PNA) binding.

Following this strategy, Giovannone et al. exposed GC B-cells to PNA to find that α2,3 sialyltransferase, ST3GAL1, was downregulated, which altered the B-cell receptor-type tyrosine phosphatase CD45 (13). Furthermore, using a series of plant lectins, the research team demonstrated that ST3GAL1 overexpression nullified PNA binding in differentiated GC B-cells and shifted the glycan composition of CD45.

Indeed, the cells exhibited a shift from extended core-2 O-glycans to truncated α2,3-sialylated T-antigen, as determined by binding affinity studies with plant lectins from Vector Laboratories, such as Maackia amurensis lectin-II (MAL-II), Jacalin, Phaseolus vulgaris leucoagglutinin (PHA-L), and Sambucus nigra agglutinin (SNA). Overall, the study established a framework of alterations in GC B-cell glycosylation and glycan profiles at different stages of differentiation.   

N-linked glycans and B-cell maturation 

Negative selection is an obstacle before cell maturation, whereby the binding of high-affinity self-antigens to B-cells can promote cell death. As previously mentioned, N-glycan branching on B-cells is a determining factor for whether or not galectins can bind and inhibit their maturation. This raises more questions about the influence of N-glycans on B-cell survival.

To that end, Mortales et al. provided further evidence that N-glycan branching is required for mature B-cell development (14). The team employed a flow cytometry protocol to detect glycan expression profiles on bone marrow B-cells stained with fluorophore-conjugated Phaseolus vulgaris leukoagglutinin (L-PHA) from Vector Laboratories. B-cells with branched N-glycans on CD19 displayed heightened signaling through their antigen receptors, stimulating positive selection and maturation. In contrast, suppressed N-glycan branching in pre-B-cells promoted a negative cell selection and eventual apoptosis.  

Interestingly, N-glycan branching can also create a seesaw effect between innate and adaptive immune responses in specific conditions. Another study by Mortales et al. showed that branching reduced pro-inflammatory innate responses by triggering the endocytosis of toll-like receptors TLR2 and TLR4, fostering adaptive immunity through increased B-cell receptor signaling in multiple sclerosis (15). 

Sialic Acid and B-cell survival 

Sialic acids are abundant on B-cell surfaces. In particular, sialoglycans have previously been associated with B-cell signaling and migration through interacting with Sialic acid binding immunoglobulin-type lectins (Siglecs). To better elucidate the role of sialic acid-siglec interactions, Linder et al. blocked sialic acid synthesis in mouse models, expecting a dampening of cell migration.

However, sialoglycan deficiency also influenced the B-cell population, unlike sialylated glycoprotein expression, which had negligible influence on cell fate. In contrast, sialoglycan deficiency caused an increase in apoptotic signals by caspase 3 and 8, giving rise to B-cell deficient mice (16). The study highlights the importance of these results for cancer cells, emphasizing the protective roles of sialoglycans against cancer cell apoptosis and implicating them as potential therapeutic targets. 

Conclusion and future directions 

The growing pool of evidence agrees on the regulatory role of glycosylation in B-cell development, differentiation, maturation, and survival. Lectin interactions with B-cell surface glycans are determining factors for the route B-cell development will follow. Therefore, future studies must connect glycomics with other omics data to improve the breadth of knowledge on glycosylation and adaptive immune response.  

Live-cell imaging has proven to be critical in evaluating the role of glycans in morphology and cellular interactions. However, the commonly used enzyme labeling methods for glycan detection in live cells still lack specificity and localization while potentially exerting cytotoxicity on the cells.

Click chemistry tools that recently gained recognition with the Nobel Prize in Chemistry 2022 hold immense potential to simplify glycoprotein labeling. More specifically, glycan epitopes of proteins are replaced with derivatives of naturally occurring monosaccharides that can bind reporter molecules through straightforward click reactions. Thus, bioconjugation of clickable monosaccharides to reporters offers non-invasive, quick, and robust glycan labeling with higher specificity (17).

Another exciting future direction in glycobiology is the integration of machine learning-aided statistical and bioinformatics tools. Thanks to the wide range of experimental data available on web interfaces, genome-wide data acquisition has been made possible.

Thus, the variety of transcriptomic and metabolomic data can be correlated to glycomics to demonstrate a holistic view of the relationship between glycans and B-cell development (18). This can be especially helpful in unlocking the multifaceted roles of B-cells in cancer progression and immune responses, which will inform the development of more effective immunotherapy strategies. 

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Original Article from Vector Labs, written by Camila Suhett PhD (Glycans and B-cells: How glycans influence adaptive immunity - Vector Laboratories (