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

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. 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.