Virus-like antigen display delivers a stand-alone danger signal through the BCR that circumvents tolerance

Abstract

How B cells discriminate self from foreign antigens remains a central question, given inherent autoreactivity of the mature B cell receptor (BCR) repertoire. Soluble antigen (sAg) induces tolerance, whereas patterned antigen display on virus-like particles (pAg) triggers robust B cell responses that can proceed without T cell help. Here, we show how this divergence arises early in BCR signaling. Unlike sAg, pAg can bypass a Lyn-dependent negative feedback loop to trigger digital signaling, such that ultra-low concentrations of pAg produce strong and sustained Ca2+ responses. Surprisingly, pAg drives maximal nuclear NF-{kappa}B but limited NFAT, whereas sAg does the opposite, reflecting differential production of diacylglycerol. Consequently, sAg induced an NFAT-dependent anergy program, whereas pAg evaded this state and instead engaged a cMyc-driven program that partially resembles a TLR-dependent danger response. Our findings reveal how proximal signaling directs distinct transcriptional fate to enable immunogenic B cell responses to virus-like antigen display.