The meninges host a distinct compartment of regulatory T cells that preserves brain homeostasis.

Our understanding of the meningeal immune system has recently burgeoned, particularly regarding how innate and adaptive effector cells are mobilized to meet brain challenges. However, information on how meningeal immunocytes guard brain homeostasis in healthy individuals remains limited. This study highlights the heterogeneous, polyfunctional regulatory T cell (Treg) compartment in the meninges. A Treg subtype specialized in controlling interferon-γ (IFN-γ) responses and another dedicated to regulating follicular B cell responses were substantial components of this compartment. Accordingly, punctual Treg ablation rapidly unleashed IFN-γ production by meningeal lymphocytes, unlocked access to the brain parenchyma, and altered meningeal B cell profiles. Distally, the hippocampus assumed a reactive state, with morphological and transcriptional changes in multiple glial cell types. Within the dentate gyrus, neural stem cells underwent more death and were blocked from further differentiation, which coincided with impairments in short-term spatial-reference memory. Thus, meningeal Tregs are a multifaceted safeguard of brain homeostasis at steady state.