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Cell Rep. 2018 Sep 25;24(13):3367-3373.e4. doi: 10.1016/j.celrep.2018.08.075.

Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers.

Author information

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.
2
Center for Autoimmune Genomics and Etiology, 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.
4
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, 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.
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.
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. Electronic address: stephen.waggoner@cchmc.org.

Abstract

Somatic hypermutation of immunoglobulin sequences in germinal center (GC) reactions must be optimized to elicit high-affinity, protective antibodies after vaccination. We expose natural killer (NK) cells as robust negative regulators of somatic hypermutation in antigen-reactive B cells. NK cells restrict follicular helper T cell (TFH) and GC B cell frequencies and titers of antigen-specific immunoglobulin after administration of alum-adjuvanted hapten-protein conjugate vaccines. This inhibition is perforin dependent, suggesting that NK cells kill one or more cells critical for GC development. 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. Thus, NK cells limit the magnitude of GC reactions and thereby restrain vaccine elicitation of high-affinity antibodies. Circumventing this activity of NK cells during vaccination has strong potential to enhance humoral immunity and facilitate vaccine-elicited prevention of disease.

KEYWORDS:

affinity maturation; germinal center; humoral immunity; immunoglobulin; innate immunity; natural killer cells; perforin; somatic hypermutation; vaccination

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