In the presence of perforin-competent NK cells, antigen-specific GC B cells acquire fewer mutations, including less frequent generation of non-synonymous substitutions and mutations associated with increased antibody affinity. This inhibition is perforin dependent, suggesting that NK cells kill one or more cells critical for GC development. NK cells restrict follicular helper T cell (T FH) and GC B cell frequencies and titers of antigen-specific immunoglobulin after administration of alum-adjuvanted hapten-protein conjugate vaccines. We expose natural killer (NK) cells as robust negative regulators of somatic hypermutation in antigen-reactive B cells. Electronic address: hypermutation of immunoglobulin sequences in germinal center (GC) reactions must be optimized to elicit high-affinity, protective antibodies after vaccination. 7 Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Immunology Graduate Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.6 Immunology Graduate Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.5 Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.4 Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.3 Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.2 Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.1 Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Immunology Graduate Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
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