Decoding immunoglobulin repertoires in zebrafish reveals distinct paradigms for adaptive immune diversification in ancient vertebrates

Nan Zhang; Chongbin Hu; Jianfei Ji; Dongdong Fan; Aifu Lin; Lixin Xiang; Ye Chen; Jianzhong Shao

doi:10.1016/j.jgg.2026.08.005

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Decoding immunoglobulin repertoires in zebrafish reveals distinct paradigms for adaptive immune diversification in ancient vertebrates

doi: 10.1016/j.jgg.2026.08.005

a. College of Life Sciences, Key Laboratory of Cell and Molecular Intelligent Design and Development of Zhejiang Province, Division of Medical Genetics and Genomics, the Children’s Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, China;
b. Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, Shandong 266071, China

Funds:

This work was supported by grants from the National Natural Science Foundation of China (U25A20726 and 32473191).

Received Date: 2026-02-08
Accepted Date: 2026-08-05
Rev Recd Date: 2026-08-04

Available Online: 2026-08-12

Abstract

Abstract

The evolutionary origins of adaptive immune diversification remain a central question in immunology. Using zebrafish as an early vertebrate model, we systematically dissect the distinct diversification strategies of ancient IgM and IgZ antibody repertoires. While both isotypes share a common V gene pool, they exhibit lineage-specific V/J usage biases during independent V(D)J recombination. Heavy-chain rearrangement employs the recombination-activating gene–non-homologous end joining (RAG–NHEJ) pathway, with IgM demonstrating greater junctional diversity than IgZ. Antigen-driven somatic hypermutation (SHM) primarily targets IgM via activation-induced cytidine deaminase (AID)-primed base excision repair/mismatch repair within primitive germinal center-like clusters. However, unbiased targeting across complementarity determining and framework regions, together with constrained CXCR5–CXCL13 signaling, limits mutation frequency and affinity maturation.Notably, we identify an AID-independent SHM pathway mediated by APOBEC2a that specifically targets TCG/CGT motifs. Furthermore, light-chain V–J recombination is uniquely processed via microhomology-mediated end joining, restricting CDR3 diversity compared with heavy-chain. Conversely, IgZ⁺ B cells are biased toward plasma cell differentiation, exhibit loosely organized distribution, and undergo minimal antigen-driven SHM, aligning with rapid mucosal defense. Our findings reveal both conserved and distinct diversification mechanisms in teleosts, illuminating layered evolutionary strategies balancing receptor diversity and self-tolerance in early vertebrates.
- Adaptive immunity,
- Diversity of immunoglobulins,
- Somatic hypermutation,
- Microhomology-directed recombination,
- Primitive germinal center

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References(52)

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