Meningeal regulatory T Cells: Gatekeepers of brain homeostasis and mediators of neuro-immunological dysfunction

Abstract

Our understanding of the meningeal immune system has expanded considerably in recent years, particularly in relation to how innate and adaptive effector immunocytes are mobilized in response to central nervous system (CNS) challenges. However, much less is known about how these cells contribute to brain homeostasis under steady-state conditions. My PhD work focuses on the heterogeneous and polyfunctional regulatory T cell (Treg) compartment in the meninges, with particular attention to its role in maintaining CNS integrity. Using a combination of flow cytometry, transcriptomic profiling, imaging, and behavioral assays, we identified functionally distinct meningeal Treg subsets, including one specialized in controlling interferon- gamma (IFN-γ) responses and another involved in the regulation of follicular B cell activity. Acute Treg ablation resulted in rapid IFN-γ production by meningeal lymphocytes, altered meningeal B cell profiles, and enabled increased immunocyte access to the brain parenchyma. These local immune changes were accompanied by reactive gliosis and transcriptional reprogramming in the hippocampus. Within the dentate gyrus, neural stem cells underwent increased cell death and failed to progress through differentiation, coinciding with deficits in short-term spatial-reference memory. Together, these findings demonstrate that meningeal Tregs act as critical, multi-functional regulators of CNS homeostasis under physiological conditions. Building on these insights, our current work investigates how meningeal Tregs respond to and potentially shape neurodegenerative disease, with a focus on Alzheimer’s disease (AD). Two parallel efforts are underway. First, we are examining how AD pathology influences the phenotype and function of meningeal Tregs in mice, and whether these cells can be modulated to alter disease progression. Second, we are characterizing the meningeal Treg compartment in human dura, comparing it to its murine counterpart and assessing how it is affected in the context of AD. These studies aim to advance our understanding of neuroimmune regulation in neurodegeneration and to explore the therapeutic potential of targeting meningeal Tregs in chronic CNS disease.