Human naïve B cells show evidence of anergy and clonal redemption following vaccination

In an era of predicted emerging pandemics, the production of effective vaccines may require an in-depth understanding of the biology of human naive B (B_N) cells. Here we provide evidence that the majority of B_N cells expressed CD73, an ecto-5'-nucleotidase often associated with immune cell suppression, and demonstrated features of anergy, including an IgM^lowIgD⁺ surface phenotype, reduced calcium flux in response to IgM crosslinking, and increased PTEN expression. Analysis of antibody sequences encoded by the inherently autoreactive V_H4-34 heavy chain produced by plasmablasts seven days following influenza vaccination showed that in younger but not in older individuals, anergic B_N cells provided a reservoir of B cells capable of responding to vaccination by somatic mutation, resulting in diversification and loss of autoreactivity. These results suggest that effective human vaccines may require the ability to awaken or 'redeem' anergic B_N cells that can be repurposed to participate in pathogen-specific responses.