Effect of interleukin-6 on IgG antibody glycosylation

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IL-6 is crucial for mounting protective T cell-dependent (TD) IgG antibody (Ab) responses but also for development of IgG-mediated autoimmune pathologies. IL-6 acts at various stages of an immune response, including the interaction between dendritic cells and CD4+ T cells and later in the germinal center (GC) reaction during Ab affinity maturation and generation of IgG subclass memory B cells and plasma cells (PCs).However, accumulating evidence suggest that not only the IgG subclass but also the structure of an N-linked glycan attached to the Fc domain of IgG Abs modulates IgG effector functions. Non-(a)galactosylated IgG Abs are associated with inflammatory actions e.g. in rheumatoid arthritis (RA) patients, whereas galactosylated plus terminal sialylated IgG Abs have reduced inflammatory potential and may suppress immune reactions.We recently showed in mice that the inflammatory environment determines the type of antigen-specific IgG glycosylation during the GC reaction by programming the CD4+ T follicular helper cell response that regulates the expression level of the corresponding glycosyltransferases in IgG+ GC B cells and PCs.However, it remains unclear what cytokine milieu is necessary for setting the GC environment for setting the IgG glycosylation pattern. Preliminary data suggest that IL-6 deficient mice fail to induce agalactosylated IgG Abs in response to strong inflammatory immunizations.We therefore hypothesise that IL-6 plays an essential role during cellular interactions prior to, and/or during, the GC reaction to set the inflammatory IgG glycosylation pattern. However, how IL-6 influences IgG glycosylation is unclear, also because IL-6 can act via three signaling routes:I) Classical-signaling describes binding of IL-6 to membrane-bound IL-6R and then to the membrane-bound signaling subunit gp130 on the same cell.II) Trans-signaling describes binding of IL-6 to soluble IL-6R, which allows activation of cells that only express gp130.III) The recently described trans-presentation describes binding of IL-6 produced e.g. by dendritic cells to IL-6R on the same cell for activating gp130 on another cell (e.g. CD4+ T cell).In this project, we will explore through which cells and signaling route(s) IL-6 modulates IgG glycosylation. We will study the effect of IL-6 on T follicular helper cell differentiation and glycosyltransferases expression in IgG+ GC B cells and PCs generated upon TD immunization by using an array of conditional knockout and transgenic mice. Finally, we will study a therapeutic effect of IL-6 interference on IgG glycosylation by blocking IL-6 signaling in autoimmune mouse models and RA patients.Together, we expect that this study would provide better understanding of the mechanisms behind differential programming of IgG glycosylation during GC-dependent responses and define a therapeutic potential of modulating IL-6 signaling to reprogram pathogenic IgG glycosylation for treating autoimmune disorders.