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

  • bioRxiv. 2026 Apr 24:2026.04.23.720482. doi: 10.64898/2026.04.23.720482.
Julianne B Riggs  1  2 ,  Alexander J Ritter  1 ,  François X P Bourassa  3 ,  Alexander R Meyer  4 ,  Erika Kay-Tsumagari  4 ,  Wei-Yun Wholey  4 ,  Jeremy Libang  1  2 ,  James L Mueller  1 ,  Wen Lu  1  5 ,  Ned S Wingreen  6  7 ,  Wei Cheng  4  8 ,  Julie Zikherman  1
Affiliations
  • 1. Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, California 94143.
  • 2. Biomedical Sciences Graduate Program, University of California, San Francisco, California 94143.
  • 3. Joseph Henry Laboratories of Physics, Princeton University, Princeton, NJ 08544.
  • 4. Department of Pharmaceutical Sciences, 1007 E. Huron Street, University of Michigan, Ann Arbor, Michigan 48104.
  • 5. current affiliation: Calico Life Sciences, South San Francisco, California 94080.
  • 6. Department of Molecular Biology, Princeton University, Princeton, NJ 08544.
  • 7. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544.
  • 8. Department of Biological Chemistry, 1150 W. Medical Center Dr., University of Michigan Medical School, Ann Arbor, Michigan 48109.
PMID: 42079227 DOI: 10.64898/2026.04.23.720482
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-κB 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.

Keywords
B cell receptor (BCR) signaling; B cell tolerance; ITIMs; Myc; NF-κB; NFAT; anergy; inhibitory co-receptors; virus-like particle; virus-like structure.
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