Marin-Rodero M, Cintado E, Walker AJ, Jayewickreme T, Pinho-Ribeiro FA, Richardson Q, Jackson R, Chiu IM, Benoist C, Stevens B, Trejo JL, Mathis D. The meninges host a distinct compartment of regulatory T cells that preserves brain homeostasis. Sci Immunol. 2025 Jan 28;:eadu2910. Epub 2025 Jan 28 PubMed.
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Washington University in St. Louis, School of Medicine
This very interesting work identifies meningeal Tregs as a unique population. It is exciting that meningeal immunity is garnering so much attention from leading immunology labs such as this one.
We have recently shown that some of the presented peptides in the dura drive suppressor T cell phenotypes (Kim et al., 2025). It is possible that combining the two concepts—suppressor and Treg expansion—could be the starting point in hopefully achieving dura-specific alteration of the immune system, as a step toward localized brain-specific immune therapy.
References:
Kim MW, Gao W, Lichti CF, Gu X, Dykstra T, Cao J, Smirnov I, Boskovic P, Kleverov D, Salvador AF, Drieu A, Kim K, Blackburn S, Crewe C, Artyomov MN, Unanue ER, Kipnis J. Endogenous self-peptides guard immune privilege of the central nervous system. Nature. 2025 Jan;637(8044):176-183. Epub 2024 Oct 30 PubMed.
View all comments by Jonathan KipnisWashington University School of Medicine
This highly novel study provides fascinating insights into the role of regulatory T cells in maintaining brain homeostasis. The identification of a distinct meningeal Treg compartment that regulates interferon-gamma (IFN-γ) responses is particularly interesting. The authors elegantly demonstrate that selective depletion of meningeal Tregs in Foxp3-DTR mice leads to a rapid expansion of lymphocytes, increased IFN-γ production, an altered meningeal immune landscape, and disruptions in hippocampal neurogenesis and cognitive function. Notably, they show that IFN-γ signaling profoundly affects the dentate gyrus, where neural stem cells exhibit increased apoptosis and reduced differentiation, ultimately impairing neurogenesis.
Their use of two distinct IL-2/antibody (IL-2/S4B6 and IL-2/Jes6-1) complex treatments highlights potential therapeutic avenues for modulating meningeal immune responses. The IL-2/S4B6 complex prevented IL-2 from binding to its high-affinity receptor, CD25, on Tregs, leading to the preferential expansion of IFN-γ–producing T cells and worsening meningeal inflammation. In contrast, the IL-2/Jes6-1 complex allowed IL-2 to bind to CD25 on Tregs, selectively expanding them and restoring immune homeostasis.
These findings extend our understanding of tissue-resident Tregs as critical regulators of neuroimmune crosstalk, with significant implications for neuroinflammatory and neurodegenerative diseases. Targeting meningeal Tregs could open new avenues for interventions in conditions such as multiple sclerosis, neurodegeneration, and cognitive decline.
View all comments by Patrick RodriguesWashington University
The meninges, especially the dura, contain a full repertoire of immune cells. However, there has been little work on the characterization and potential role of the T regulatory cell (Treg) compartment. In other organs, Tregs can restrain immune responses. In this elegant paper, Miguel Marin-Rodero, from the lab of Diane Mathis, and colleagues assess the role of Tregs and meningeal Tregs in the normal mouse brain. They find that soon after Treg ablation there was an increase in IFN-γ responses and production in immunocytes in the meninges. Evidence indicated that this effect was due to meningeal Treg depletion.
These changes resulted in several changes in the brain, mostly in the hippocampus, including increased T cell entry, a more reactive state of microglia and astrocytes, increased neural stem cell death, and impaired short-term memory performance. These results suggest an important normal role for Tregs in the meninges, where these and other immune cells appear to play key roles in immune/brain homeostasis.
These findings immediately raise a number of questions in regard to CNS diseases, particularly neurodegenerative ones. Do Tregs, specifically meningeal Tregs, influence similar processes in the setting of neurodegeneration? If so, are similar mechanisms at play regarding their ability to regulate IFN-γ responses and production in the meninges, brain T cell infiltration, and cell death within the hippocampus? Can regulation of meningeal Tregs serve as a therapeutic target? While Tregs have been shown to play a role in experimental models of stroke, the specific role of meningeal Tregs, and Tregs in general, in neurodegenerative diseases such as AD, FTD, and Lewy body disease is virtually unexplored. This work opens the stage for many exciting future studies.
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