Assistant Professor Albert Einstein College of Medicine Bronx, New York, United States
Introduction/Rationale: B-cell fate and antibody output are not determined by intrinsic programs alone but are shaped by tissues in which B cells are activated and selected. Classical models emphasize germinal center–driven affinity optimization, but inflamed and metabolically stressed tissues present conditions that challenge these rules. We identified microenvironmental niches rewiring B-cell selection, diversification, and antibody isotope landscape – mechanisms which operate across metabolic disease and cancer.
Methods: We combined genetic fate mapping and adoptive-transfer models to interrogate germinal center invasion, somatic mutation, while inflammatory B-cell subsets were functionally tested using B-cell-specific transcriptional perturbations and serum transfers. These approaches were combined with analyses in cancer using single-cell profiling and isotype-resolved immune mapping.
Results: We found that B-cell selection is dynamic and environmentally tuned. Naïve B cells continuously invade germinal centers, particularly when antibody feedback lowers affinity thresholds, promoting diversification. In inflamed adipose tissue, chronic metabolic stress drives T-bet+ B cell accumulation that produce pathogenic IgG driving inflammation and systemic metabolic dysfunction. Genetic ablation of T-bet in B cells ameliorates disease demonstrating pathogenic tissue-driven B-cell differentiation.
Conclusion: Our studies establish that tissue microenvironments actively rewrite B-cell selection rules, prioritizing diversification or inflammatory antibody production depending on local pressures. This plasticity provides insights into how antibody responses can be adaptive in vaccination yet pathogenic in chronic inflammatory disease. Similar selection pressures operate within the tumor microenvironment, where we identified unexpected inflammation- and metabolic-stress pathways that dictate B-cell fate and isotype architecture.
