Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers
Summary: 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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-09-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718313792 |
| _version_ | 1818172470801203200 |
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| author | Carolyn E. Rydyznski Stacey A. Cranert Julian Q. Zhou Heping Xu Steven H. Kleinstein Harinder Singh Stephen N. Waggoner |
| author_facet | Carolyn E. Rydyznski Stacey A. Cranert Julian Q. Zhou Heping Xu Steven H. Kleinstein Harinder Singh Stephen N. Waggoner |
| author_sort | Carolyn E. Rydyznski |
| collection | DOAJ |
| description | Summary: 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. : Natural killer (NK) cells limit immunization-elicited follicular helper T cell and germinal center B cell responses. Rydyznski et al. link perforin-dependent functions of NK cells to a reduced frequency and quality of somatic hypermutation within antigen-specific B cells. Strategies targeting this NK cell activity may enhance vaccination-induced generation of high-affinity protective antibodies. Keywords: natural killer cells, germinal center, vaccination, affinity maturation, perforin, somatic hypermutation, immunoglobulin, humoral immunity, innate immunity |
| first_indexed | 2024-12-11T19:13:08Z |
| format | Article |
| id | doaj.art-1bcdeda46d92478ea8824617a00cc1ef |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T19:13:08Z |
| publishDate | 2018-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-1bcdeda46d92478ea8824617a00cc1ef2022-12-22T00:53:43ZengElsevierCell Reports2211-12472018-09-01241333673373.e4Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal CentersCarolyn E. Rydyznski0Stacey A. Cranert1Julian Q. Zhou2Heping Xu3Steven H. Kleinstein4Harinder Singh5Stephen N. Waggoner6Center 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, USACenter for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USAInterdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USADivision of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USAInterdepartmental 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, USAImmunology 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, USACenter 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; Corresponding authorSummary: 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. : Natural killer (NK) cells limit immunization-elicited follicular helper T cell and germinal center B cell responses. Rydyznski et al. link perforin-dependent functions of NK cells to a reduced frequency and quality of somatic hypermutation within antigen-specific B cells. Strategies targeting this NK cell activity may enhance vaccination-induced generation of high-affinity protective antibodies. Keywords: natural killer cells, germinal center, vaccination, affinity maturation, perforin, somatic hypermutation, immunoglobulin, humoral immunity, innate immunityhttp://www.sciencedirect.com/science/article/pii/S2211124718313792 |
| spellingShingle | Carolyn E. Rydyznski Stacey A. Cranert Julian Q. Zhou Heping Xu Steven H. Kleinstein Harinder Singh Stephen N. Waggoner Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers Cell Reports |
| title | Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers |
| title_full | Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers |
| title_fullStr | Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers |
| title_full_unstemmed | Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers |
| title_short | Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers |
| title_sort | affinity maturation is impaired by natural killer cell suppression of germinal centers |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718313792 |
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