Sialic acids on B cells are crucial for their survival and provide protection against apoptosis.

Sialic acids (Sias) on the B cell membrane are involved in cell migration, in the control of the complement system and, as sialic acid-binding immunoglobulin-like lectin (Siglec) ligands, in the regulation of cellular signaling. We studied the role of sialoglycans on B cells in a mouse model with B cell-specific deletion of cytidine monophosphate sialic acid synthase (CMAS), the enzyme essential for the synthesis of sialoglycans. Surprisingly, these mice showed a severe B cell deficiency in secondary lymphoid organs. Additional depletion of the complement factor C3 rescued the phenotype only marginally, demonstrating a complement-independent mechanism. The B cell survival receptor BAFF receptor was not up-regulated, and levels of activated caspase 3 and processed caspase 8 were high in B cells of Cmas-deficient mice, indicating ongoing apoptosis. Overexpressed Bcl-2 could not rescue this phenotype, pointing to extrinsic apoptosis. These results show that sialoglycans on the B cell surface are crucial for B cell survival by counteracting several death-inducing pathways.

Sialic acids on T cells are crucial for their maintenance and survival.

Sialic acids are found as terminal sugars on glycan structures on cellular surfaces. T cells carry these sialoglycans abundantly, and they are thought to serve multiple functions in cell adhesion, cell migration, and protection from complement attack. We studied the role of sialoglycans on T cells in a mouse model with a T cell-specific deletion of cytidine monophosphate-sialic acid synthase (CMAS), the enzyme that is crucial for the synthesis of sialoglycans. These mice showed a T-cell deficiency in peripheral lymphoid organs. Many T cells with an undeleted Cmas allele were found in the periphery, suggesting that they escaped the Cre-mediated deletion. The remaining peripheral T cells of T cell-specific Cmas KO mice had a memory-like phenotype. Additional depletion of the complement factor C3 could not rescue the phenotype, showing that the T-cell defect was not caused by a host complement activity. Cmas-deficient T cells showed a high level of activated caspase 3, indicating an ongoing apoptosis. In bone marrow chimeric cellular transfer experiments, we observed a strong competitive disadvantage of Cmas-deficient T cells compared to wild-type T cells. These results show that sialoglycans on the surface of T cells are crucial for T-cell survival and maintenance. This function has not been recognized before and is similar to the function of sialoglycans on B cells.

Primary Immune Responses and Affinity Maturation Are Controlled by IgD.

Mature B cells co-express IgM and IgD B cell antigen receptors (BCR) on their surface. While IgM BCR expression is already essential at early stages of development, the role of the IgD-class BCR remains unclear as most B cell functions appeared unchanged in IgD-deficient mice. Here, we show that IgD-deficient mice have an accelerated rate of B cell responsiveness as they activate antibody production within 24h after immunization, whereas wildtype (WT) animals required 3 days to activate primary antibody responses. Strikingly, soluble monovalent antigen suppresses IgG antibody production induced by multivalent antigen in WT mice. In contrast, IgD-deficient mice were not able to modulate IgG responses suggesting that IgD controls the activation rate of B cells and subsequent antibody production by sensing and distinguishing antigen-valences. Using an insulin-derived peptide we tested the role of IgD in autoimmunity. We show that primary autoreactive antibody responses are generated in WT and in IgD-deficient mice. However, insulin-specific autoantibodies were detected earlier and caused more severe symptoms of autoimmune diabetes in IgD-deficient mice as compared to WT mice. The rapid control of autoimmune diabetes in WT animals was associated with the generation of high-affinity IgM that protects insulin from autoimmune degradation. In IgD-deficient mice, however, the generation of high-affinity protective IgM is delayed resulting in prolonged autoimmune diabetes. Our data suggest that IgD is required for the transition from primary, highly autoreactive, to secondary antigen-specific antibody responses generated by affinity maturation.

B Cell Siglecs-News on Signaling and Its Interplay With Ligand Binding.

CD22 and Siglec-G are members of the Siglec family. Both are inhibitory co-receptors on the surface of B cells and inhibit B-cell receptor induced signaling, characterized by inhibition of the calcium mobilization and cellular activation. CD22 functions predominantly as an inhibitor on conventional B cells, while Siglec-G is an important inhibitor on the B1a-cell subset. These two B-cell Siglecs do not only inhibit initial signaling, but also have an important function in preventing autoimmunity, as double deficient mice develop a lupus-like phenotype with age. Siglecs are characterized by their conserved ability to bind terminal sialic acid of glycans on the cell surface, which is important to regulate the inhibitory role of Siglecs. While CD22 binds α2,6-linked sialic acids, Siglec-G can bind both α2,6-linked and α2,3-linked sialic acids. Interestingly, ligand binding is differentially regulating the ability of CD22 and Siglec-G to control B-cell activation. Within the last years, quite a few studies focused on the different functions of B-cell Siglecs and the interplay of ligand binding and signal inhibition. This review summarizes the role of CD22 and Siglec-G in regulating B-cell receptor signaling, membrane distribution with the importance of ligand binding, preventing autoimmunity and the role of CD22 beyond the naïve B-cell stage. Additionally, this review article features the long time discussed interaction between CD45 and CD22 with highlighting recent data, as well as the interplay between CD22 and Galectin-9 and its influence on B-cell receptor signaling. Moreover, therapeutical approaches targeting human CD22 will be elucidated.