IgG Fc sialylation is regulated during the germinal center reaction following immunization with different adjuvants
Authors: Yannic C. Bartsch, Simon Eschweiler, Alexei Leliavski, Hanna B. Lunding, Sander Wagt, Janina Petry, Gina-Maria Lilienthal, Johann Rahmöller, Noortje de Haan, Alexandra Hölscher, Raghu Erapaneedi, Anastasios D. Giannou, Lilian Aly, Ryota Sato, Louise A. de Neef, André Winkler, Dominique Braumann, Juliane Hobusch, Kyra Kuhnigk, Vanessa Krémer, Moritz Steinhaus, Véronique Blanchard, Timo Gemoll, Jens K. Habermann, Mattias Collin, Gabriela Salinas, Rudolf A. Manz, Hidehiro Fukuyama, Thomas Korn, Ari Waisman, Nir Yogev, Samuel Huber, Björn Rabe, Stefan Rose-John, Hauke Busch, Friederike Berberich-Siebelt, Christoph Hölscher, Manfred Wuhrer, Marc Ehlers
Journal: Journal of Allergy and Clinical Immunology (2020)

BackgroundEffector functions of IgG Abs are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory (auto)immune disorders and have also been linked to protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects.ObjectiveWe sought to investigate IgG glycosylation programming during the germinal center (GC) reaction following immunization of mice with a foreign protein antigen and different adjuvants.MethodsMice were analyzed for GC T-cell, B-cell, and plasma cell responses, as well as for antigen-specific serum IgG subclass titers and Fc glycosylation patterns.ResultsDifferent adjuvants induce distinct IgG+ GC B-cell responses with specific transcriptomes and expression levels of the α2,6-sialyltransferase responsible for IgG sialylation that correspond to distinct serum IgG Fc glycosylation patterns. Low IgG Fc sialylation programming in GC B cells was overall highly dependent on the Foxp3– follicular helper T (TFH) cell–inducing cytokine IL-6, here in particular induced by water-in-oil adjuvants and Mycobacterium tuberculosis. Furthermore, low IgG Fc sialylation programming was dependent on adjuvants that induced IL-27 receptor–dependent IFN-γ+ TFH1 cells, IL-6/IL-23–dependent IL-17A+ TFH17 cells, and high ratios of TFH cells to Foxp3+ follicular regulatory T cells. Here, the 2 latter were dependent on M tuberculosis and its cord factor.ConclusionThis study's findings regarding adjuvant-dependent GC responses and IgG glycosylation programming may aid in the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns in the GC. Effector functions of IgG Abs are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory (auto)immune disorders and have also been linked to protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects. We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction following immunization of mice with a foreign protein antigen and different adjuvants. Mice were analyzed for GC T-cell, B-cell, and plasma cell responses, as well as for antigen-specific serum IgG subclass titers and Fc glycosylation patterns. Different adjuvants induce distinct IgG+ GC B-cell responses with specific transcriptomes and expression levels of the α2,6-sialyltransferase responsible for IgG sialylation that correspond to distinct serum IgG Fc glycosylation patterns. Low IgG Fc sialylation programming in GC B cells was overall highly dependent on the Foxp3– follicular helper T (TFH) cell–inducing cytokine IL-6, here in particular induced by water-in-oil adjuvants and Mycobacterium tuberculosis. Furthermore, low IgG Fc sialylation programming was dependent on adjuvants that induced IL-27 receptor–dependent IFN-γ+ TFH1 cells, IL-6/IL-23–dependent IL-17A+ TFH17 cells, and high ratios of TFH cells to Foxp3+ follicular regulatory T cells. Here, the 2 latter were dependent on M tuberculosis and its cord factor. This study's findings regarding adjuvant-dependent GC responses and IgG glycosylation programming may aid in the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns in the GC.