ST6Gal1 in plasma is dispensable for IgG sialylation.

The glycosylation of immunoglobulin G (IgG) has attracted increased attention due to the impact of N-glycan modifications at N297 on IgG function, acting primarily through modulation of Fc domain conformation and Fcγ receptor-binding affinities and signaling. However, the mechanisms regulating IgG glycosylation and especially α2,6-sialylation of its N-glycan remain poorly understood. We observed previously that IgG is normally sialylated in mice with B cells lacking the sialyltransferase ST6Gal1.

Disruption of hepatocyte Sialylation drives a T cell-dependent pro-inflammatory immune tone.

Through the catalysis of α2,6-linked sialylation, the enzyme ST6Gal1 is thought to play key roles in immune cell communication and homeostasis. Of particular importance, glycans with terminal α2,6-sialic acids are known to negatively regulate B cell receptor signaling and are associated with an immunosuppressive tumor microenvironment that promotes T cell anergy, suggesting that α2,6-sialic acids are a key immune inhibitory signal. Consistent with this model, mice harboring a hepatocyte-specific ablation of ST6Gal1 (H-cKO) develop a progressive and severe non-alcoholic fatty liver disease characterized by steatohepatitis.

Modulation of hepatocyte sialylation drives spontaneous fatty liver disease and inflammation.

Circulatory protein glycosylation is a biomarker of multiple disease and inflammatory states and has been applied in the clinic for liver dysfunction, heart disease and diabetes. With the notable exception of antibodies, the liver produces most of the circulatory glycoproteins, including the acute phase proteins released as a function of the inflammatory response. Among these proteins is β-galactoside α2,6-sialyltransferase (ST6Gal1), an enzyme required for α2,6-linked sialylation of glycoproteins.

Plasma glycomics predict cardiovascular disease in patients with ART-controlled HIV infections.

Despite effective control of HIV infection with antiretroviral drugs, individuals with HIV have high incidences of secondary diseases. These sequelae, such as cardiovascular disease (CVD), are poorly understood and represent a major health burden. To date, predictive biomarkers of HIV-associated secondary disease have been elusive, making preventative clinical management essentially impossible.

The Glycoscience of Immunity.

Carbohydrates, or glycans, are as integral to biology as nucleic acids and proteins. In immunology, glycans are well known to drive diverse functions ranging from glycosaminoglycan-mediated chemokine presentation and selectin-dependent leukocyte trafficking to the discrimination of self and non-self through the recognition of sialic acids by Siglec (sialic acid-binding Ig-like lectin) receptors. In recent years, a number of key immunological discoveries are driving a renewed and burgeoning appreciation for the importance of glycans.

Emerging glycobiology tools: A renaissance in accessibility.

The glycobiology of the immune response is a topic that has garnered increased attention due to a number of key discoveries surrounding IgG function, the specificity of some broadly neutralizing anti-HIV antibodies, cancer immunoregulation by galectin molecules and others. This review is the opening article in a Special Edition of Cellular Immunology focused on glycoimmunology, and has the goal of setting the context for these articles by providing a mini-review of how glycans impact immunity. We also focus on some of the technological and methodological advances in the field of glycobiology that are being deployed to lower the barrier of entry into the glycosciences, and to more fully interrogate the glycome and its function.

T cell-intrinsic TLR2 stimulation promotes IL-10 expression and suppressive activity by CD45RbHi T cells.

While Toll-like receptors (TLRs) represent one of the best characterized innate immune pathways, evidence suggests that TLRs are not restricted to innate leukocytes and some epithelial cells, but are also expressed in T cells. Specifically, published evidence focusing on FoxP3+ regulatory T cells demonstrate that they express functional TLR2, which is already known among the TLR family for its association with immune suppression; however, little is known about the relationship between T cell-intrinsic TLR2 binding and cytokine production, T cell differentiation, or T cell receptor (TCR) stimulation. Here, we demonstrate that TCR and TLR2 co-stimulation provides a T cell-intrinsic signal which generates a dramatic, synergistic cytokine response dominated by IL-10.

B-cell-independent sialylation of IgG.

IgG carrying terminal α2,6-linked sialic acids added to conserved N-glycans within the Fc domain by the sialyltransferase ST6Gal1 accounts for the anti-inflammatory effects of large-dose i.v. Ig (IVIg) in autoimmunity.