Journal
CELL
Volume 162, Issue 1, Pages 160-169Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.06.026
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Funding
- National Institute of Allergy And Infectious Diseases of the NIH [U19AI111825, U19AI109946]
- Rockefeller University Clinical Scholar
- Iris and Junming Le Foundation
- Rockefeller University Center for Clinical and Translational Science grant from the National Center for Advancing Translational Sciences, NIH [UL1 TR000043]
- Clinical and Translational Science Award program
- Centers of Excellence for Influenza Research and Surveillance [HHSN266200700010C]
- Rockefeller University
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Protective vaccines elicit high-affinity, neutralizing antibodies by selection of somatically hypermutated B cell antigen receptors (BCR) on immune complexes (ICs). This implicates Fc-Fc receptor (FcR) interactions in affinity maturation, which, in turn, are determined by IgG subclass and Fc glycan composition within ICs. Trivalent influenza virus vaccination elicited regulation of anti-hemagglutinin (HA) IgG subclass and Fc glycans, with abundance of sialylated Fc glycans (sFc) predicting quality of vaccine response. We show that sFcs drive BCR affinity selection by binding the Type-II FcR CD23, thus upregulating the inhibitory Fc gamma RIIB on activated B cells. This elevates the threshold requirement for BCR signaling, resulting in B cell selection for higher affinity BCR. Immunization with sFc HA ICs elicited protective, high-affinity IgGs against the conserved stalk of the HA. These results reveal a novel, endogenous pathway for affinity maturation that can be exploited for eliciting high-affinity, broadly neutralizing antibodies through immunization with sialylated immune complexes.
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