Origin, fate, and function of meningeal mature and progenitor B cells.

• Applicant: Privatdozent Dr. Gerd Meyer zu Hörste
• Subject Area: Developmental Neurobiology ; Immunology ; Clinical Neurology; Neurosurgery and Neuroradiology ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452509166

The central nervous system (CNS) is ensheathed by the cerebrospinal fluid (CSF) and fibrous membranes termed meninges. Both serve immune-related functions, but the composition and function of lymphocytes residing in these CNS-associated border compartments is poorly defined. In own previous results, we made three key observations: 1) the lymphocyte composition in each CNS-associated border compartment compartment is unique, 2) even the homeostatic dura, but no other compartment, contains abundant B cells, 3) surprisingly, healthy rodent dura also contains B cell progenitors at the pro-B cell stage. In further follow-up experiments, we confirmed the propensity of the dura to host B cells in experimental neuroinflammation. We also observed that the transcription factor Bcl6 serves non-canonical functions in Th17 cells by promoting B cell-dominated meningeal inflammation. We thereby identified a key mechanism controlling the compartmentalization of meningeal vs. parenchymal inflammation. Based on these previous observations, we here plan to understand the origin, fate, and function of meningeal and skull BM-resident B cells and B cell progenitors. The key technical challenge in this context is to achieve location-specific labelling and modulation of leukocytes. In preparation for this challenge of the present proposal, we have established trans-skull bone and intra-skull labelling with tracer dyes and photoconversion of meningeal and skull bone marrow B cells expressing a photoconvertible fluorescent protein. We also acquired ressources to deplete B cells in a site-specific manner. With this experimental ‘toolkit’ we now aim to address whether meningeal B cells and B cell progenitors originate directly from the skull bone marrow or from secondary lymphoid organs and where they traffic from the meninges. We will then test the functional relevance of meningeal B cells in neuro-inflammation by applying small molecule inhibitor through the trans-skull route and injecting anti-CD20 B cell-depleting antibodies into the cisterna magna. Finally we aim to identify novel mechanisms controlling meningeal residency of B cells in a deep transcriptional characterization. We will validate novel candidates using an in vitro ‘flipped skull’ culture system and potentially in vivo using site-specific approaches for inhibition. We will thereby study the origin, fate, and function of meningeal mature and progenitor B cells.

• DFG Programme: Research Grants