BCR signal strength governs VH gene replacement in peripheral B cells.

Authors

Monika Vashisht, Huaibin Ge, Karen Siddoway, Jessy John, Harlie A McKelvey, Rui Dong, Mohammad A I Al-Hatamleh, Alexandra Krinsky, Vince Popolizio, Alondra M Ware, Gero Knittel, Hans Christian Reinhardt, Zhangguo Chen, Jing H Wang

Published in

Cellular & molecular immunology. Oct 09, 2026. Epub Oct 09, 2026.

Abstract

Generated by stochastic V(D)J recombination, unique B-cell receptors (BCRs) consist of IgH and IgL chains, recognize antigens, and serve as distinct barcodes to identify each individual B cell. Once a B-cell acquires its BCR, does it maintain its identity, or does a peripheral B-cell ever rearrange its BCR again? Under what circumstances a peripheral B-cell would undergo secondary V(D)J recombination at its Igh locus, termed V_H gene replacement (VHR), remains poorly understood. Using hen egg lysozyme (HEL) BCR knock-in mice, we observed that when the BCR cannot bind to any foreign or self-antigen, peripheral B cells upregulate the expression of the VDJ recombinase RAG-1 and undergo VHR to acquire new BCRs and become non-HEL-binding. TRAF3 deficiency increased the frequency of VHR-experienced B cells and predisposed them to abnormal oligoclonal expansion by preventing B cells from dying from RAG-initiated DNA double-stranded breaks in an NF-κB2-dependent manner. Engaging the HEL BCR or inhibiting proximal BCR signaling modulated RAG-1 expression. The frequency of VHR was substantially inhibited by enhanced BCR signaling caused by a gain-of-function mutant allele of Cd79b, a signaling component of the BCR complex. We conclude that BCR signaling strength influences the probability of a given B-cell undergoing VHR. Furthermore, signaling molecules such as TRAF3 can serve as nonclassical checkpoints to maintain B-cell genome stability during VHR. Our studies provide fundamental insights into the mechanisms underlying the dynamic regulation of antigen receptor identity in peripheral B cells, with implications for immune tolerance and B-cell homeostasis. Our studies reveal novel mechanisms of genomic instability in VHR-experienced peripheral B cells and provide fundamental insights into the conditions under which B cells alter their identity via VHR, as well as the regulatory mechanisms governing the VHR process.

PMID:
42855489
Bibliographic data and abstract were imported from PubMed on 10 Oct 2026.

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