Conserved interactions with stromal and immune cells coordinate de novo B cell lymphopoiesis in fetal intestines.

Recent findings suggest that the small intestine (SI) is a potentially novel site for B cell lymphopoiesis during fetal and neonatal life. However, the unique and/or conserved features that enable B cell development at this site remain unclear. To investigate the molecular and cellular scaffolds for B cell lymphopoiesis in mouse and human fetal intestines, we leveraged single-cell RNA-Seq, in situ immunofluorescence, spatial transcriptomics, and high-dimensional spectral flow cytometry. We found that SI mesenchymal and stromal cells expressed higher levels of chemokines known to recruit common lymphoid progenitors. Importantly, local lymphatic endothelial cells expressed IL-7 and TSLP in proximity to IL-7R+ precursor B cells, likely promoting their differentiation in the SI. Notably, we found that fetal-derived lymphoid tissue inducer (LTi) cells were required for B cell development and localization in the SI, but not fetal liver. These findings identify a lymphoid tissue development-independent role for this immune cell in B cell development. Collectively, our data reveal a conserved intestinal B cell niche in mice and humans, challenging traditional models of lymphopoiesis. The identification of a requisite cellular/molecular scaffold for fetal B cell development allows future studies to test the importance of this de novo B cell lymphopoiesis to long-term immunity.