Akerstrand, H. | Search bioRxiv

bioRxiv2026

The early-life determinant LIN28B constrains immunoglobulin light chain secondary rearrangements independent of BCR specificity

The early-life B cell repertoire is disproportionately enriched for self-reactive specificities in mice and humans, raising the question of how this ontogenic permissiveness is achieved. The predominant B cell central tolerance mechanism edits away self-reactivity by secondary rearrangements of the immunoglobulin light chain (IgL) following strong B cell receptor (BCR) engagement during the immature B cell stage. Here, we demonstrate a layer of developmental regulation, imposed by the early-life restricted RNA-binding protein LIN28B, that suppresses the incidence and capacity for IgL secondary rearrangements during ontogeny. Genetic dissection demonstrated that the underlying mechanisms operate independent of BCR specificity or pre-BCR requirement, dissociating the receptor editing fate from strict BCR instruction. We identified an adult-specific receptor editing-biased pre-B cell state marked by CD25 expression and metabolic quiescence. LIN28B subverted this state, shifting the balance from secondary rearrangements to positive selection and bone marrow egress. Together, our results demonstrate that the central tolerance threshold is an ontogenically tuned parameter, providing insights into the self-reactivity bias that characterizes the early-life B cell repertoire.

immunology↗

bioRxiv2022

Enhanced protein synthesis is a defining requirement for neonatal B cell development

The LIN28B RNA binding protein exhibits a ontogenically restricted expression pattern and is a key molecular regulator of fetal and neonatal B lymphopoiesis. It enhances the positive selection of CD5+ immature B cells early in life through amplifying the CD19/PI3K/c-MYC pathway and is sufficient to reinitiate self-reactive B-1a cell output when ectopically expressed in the adult. In this study, interactome analysis in primary B cell precursors showed direct binding by LIN28B to numerous ribosomal protein transcripts, consistent with a regulatory role in cellular protein synthesis. Induction of LIN28B expression in the adult setting is sufficient to promote enhanced protein synthesis during the small Pre-B and immature B cell stages, but not during the Pro-B cell stage. This stage dependent effect was dictated by IL-7 mediated signaling, which masked the impact of LIN28B through an overpowering stimulation on the c-MYC / protein synthesis axis in Pro-B cells. Importantly, elevated protein synthesis was a distinguishing feature between neonatal and adult B cell development that was critically supported by endogenous Lin28b expression early in life. Finally, we used a ribosomal hypomorphic mouse model to demonstrate that subdued protein synthesis is specifically detrimental for neonatal B lymphopoiesis and the output of B-1a cells, without affecting B cell development in the adult. Taken together, we identify elevated protein synthesis as a defining requirement for early-life B cell development that critically depends on Lin28b. Our findings offer new mechanistic insights into the layered formation of the complex adult B cell repertoire.

immunology↗