UCSF

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. In this thesis, my colleagues and I take advantage of a set of neutral liposomes of viral size that are engineered to display affinity mutants of the model antigen (Ag) hen egg lysozyme at precisely varied density. We show, by contrast to soluble antigen (sAg), that particulate virus-like Ag (pAg) display by liposomes induces highly potent B cell responses that are dose- and density-dependent but affinity-independent. We show how this divergence in potency between sAg and pAg 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-kB 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. Finally, though pAg-stimulated cells do not require T cell help to produce immunogenic responses, they nevertheless can incorporate Ag-specific T cells into an immunogenic response and are also capable of reactivating anergic B cells. Our findings reveal how proximal signaling directs distinct transcriptional fate to enable immunogenic B cell responses to virus-like antigen display.