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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.

SUBMITTER: Rydyznski CE 

PROVIDER: S-EPMC6192537 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Rydyznski Carolyn E CE   Cranert Stacey A SA   Zhou Julian Q JQ   Xu Heping H   Kleinstein Steven H SH   Singh Harinder H   Waggoner Stephen N SN  

Cell reports 20180901 13


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 (T<sub>FH</sub>) and GC B cell frequencies and titers of antigen-specific immunoglobulin after administration of alum-adjuvanted hapten-protein conjugate vaccines. This  ...[more]

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