Early developing B cells undergo negative selection by central nervous system-specific antigens in the meninges.

Self-reactive B cell progenitors are eliminated through central tolerance checkpoints, a process thought to be restricted to the bone marrow in mammals. Here, we identified a consecutive trajectory of B cell development in the meninges of mice and non-human primates. The meningeal B cells were located predominantly at the dural sinuses, where endothelial cells expressed essential niche factors to support B cell development. Parabiosis experiments together with lineage tracing showed that meningeal developing B cells were replenished continuously from hematopoietic stem cell (HSC)-derived progenitors via a circulation-independent route. Autoreactive immature B cells that recognized myelin oligodendrocyte glycoprotein (MOG), a central nervous system-specific antigen, were eliminated specifically from the meninges. Furthermore, genetic deletion of the Mog gene restored the self-reactive B cell population in the meninges. These findings identify the meninges as a distinct reservoir for B cell development, allowing in situ negative selection to ensure a locally non-self-reactive immune repertoire. [Display omitted] • Early developing B cells are present in the meninges of mice and non-human primates • HSC-derived progenitors in the skull replenish meningeal developing B cells • CNS-reactive immature B cells are eliminated specifically from the meninges • Genetic deletion of Mog restores the self-reactive B cell population in the meninges Self-reactive B cell progenitors are eliminated through central tolerance checkpoints, a process thought to be restricted to the bone marrow. Wang et al. show that developing B cells in the meninges undergo a central nervous system (CNS) antigen-dependent checkpoint to prevent autoreactive B cells from accumulating at the CNS borders. [ABSTRACT FROM AUTHOR]