Early life fibroblast niches orchestrate B lymphopoiesis at the brain’s borders 4751

Abstract Description We set out to map the development of brain border immune compartments and, surprisingly, uncovered a wave of B cells that expand in the dura and leptomeninges shortly after birth. Single cell RNA sequencing revealed that early life B cells undergo lymphopoiesis in the meninges, which occurs in concert with waves of extramedullary lymphopoiesis across the body. Using DNA barcoding and CreER-based fate mapping approaches, we found that meningeal and other early life B cells are seeded by a common pool of embryonic progenitors that diverge perinatally and generate self-sufficient waves of B cell development. In the dura, developing B cells associate with anatomically and molecularly defined populations of fibroblasts near the dural sinuses. These fibroblasts produce chemokines, growth factors, and extracellular matrix components that crosstalk with developing B cells and ablation of niche factors from meningeal fibroblasts disrupts local B lymphopoiesis. This fibroblast niche is remodeled in adulthood and loses expression of niche factors, suggesting that the meninges are exquisitely tuned to support B lymphopoiesis in early life. This data suggests that CNS border tissues contribute to generation of the postnatal B cell compartment and provides a model for how extramedullary stromal niches may regulate B lymphopoiesis in early life. Ongoing studies aim to explore upstream factors that imprint this neonatal fibroblast niche and the role of this niche in early life CNS infection. Funding Sources Howard Hughes Medical Institute Investigator Program (Beth Stevens) Topic Categories Neuroimmunology (NEUR)