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Abstract

A considerable proportion of peripheral B cells is autoreactive, and it is unclear how the activation of such potentially harmful cells is regulated. In this study, we show that the different activation thresholds or IgM and IgD BCRs adjust B cell activation to the diverse requirements during development. We rely on the autoreactive 3-83 model BCR to generate and analyze mice expressing exclusively autoreactive IgD BCRs on two different backgrounds that determine two stages of autoreactivity, depending on the presence or absence of the cognate Ag. By comparing these models with IgM-expressing control mice, we found that, compared with IgM, IgD has a higher activation threshold in vivo, as it requires autoantigen to enable normal B cell development, including allelic exclusion. Our data indicate that IgM provides the high sensitivity required during early developmental stages to trigger editing of any autoreactive specificities, including those enabling weak interaction with autoantigen. In contrast, IgD has the unique ability to neglect weakly interacting autoantigens while retaining reactivity to higher-affinity Ag. This IgD function enables mature B cells to ignore autoantigens while remaining able to efficiently respond to foreign threats.