The in utero experience of NOD fetuses imprints disposition of B- and T-cell populations, autoantibody patterns, and diabetes development

Maternal factors during fetal development may influence the onset and progression of autoimmune diseases such as type 1 diabetes (T1D). Using the non-obese diabetic (NOD) mouse model, we investigated whether the in utero environment affects diabetes incidence, pancreatic insulitis, autoantibody profiles, and lymphocyte composition. NOD embryos were transferred to C57BL/6 (B6) females, generating NOD/B6 offspring, and reciprocal transfers produced B6/NOD mice. Diabetes incidence was monitored for 52 weeks, and immune parameters were analyzed at 7-11 weeks of age using immunofluorescence, ELISA, and flow cytometry. NOD/B6 mice exhibited a ~50% reduction in cumulative diabetes incidence compared to NOD controls, despite similar insulitis severity. Serum analysis revealed significantly increased IgM titers against insulin, DNA, and GAD65 in NOD/B6 mice relative to NOD mice, along with altered IgG subclass distributions, including elevated IgG1 and IgG2c levels. UMAP and ROC analyses confirmed that distinct IgG subclass patterns were influenced by the maternal environment. Furthermore, NOD/B6 mice displayed an intermediate phenotype in B cell subset distribution and a notable increase in CD4⁺CD25⁺ regulatory T cells (Tregs) in the blood and spleen, with restored CD25 expression compared to NOD mice. Marginal zone B cells as well as thymic B cell proportions were reduced in NOD/B6 relative to NOD, whereas bone marrow B cell development remained unaffected. These findings demonstrate that maternal factors imprint long-term changes in adaptive immunity and modulate diabetes susceptibility in NOD mice. The observed alterations in antibody profiles and the Treg population suggest that transplacental influences contributed to immune regulation beyond genetic predisposition, highlighting a potential non-genetic contributing factor in T1D pathogenesis.