From the Meninges, Regulatory T Cells Keep Brain Inflammation in Check
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Stationed within the meninges, squads of immune cells lie in wait, ready to unleash an inflammatory assault within the brain if needed. Holding these trigger-happy troops back during peacetime falls to a sparse population of regulatory T cells, according to a paper published January 28 in Science Immunology. These Tregs are potent. When scientists led by Diane Mathis at Harvard Medical School in Boston depleted meningeal Tregs in mice, those other immune cells sprang to action, churning out cytokines and infiltrating the brain parenchyma.
- A sparse population of regulatory T cells inhabits the meninges of the mouse brain.
- Depleting them allows other T cells to infiltrate the brain, unleashing inflammation in the hippocampus.
- The invading T cells secrete interferon-γ, compromising neurogenesis and memory.
This response was strongest in the hippocampus, where immune infiltrators kicked astrocytes and microglia into reactive states. IFN-γ produced by T cells killed fledgling neural stem cells, putting the kibosh on neurogenesis and messing with memory. The study underscores the destructive power of meningeal immune cells, and casts Tregs as peacekeepers, protecting the brain from preemptive strikes.
“This very interesting work identifies meningeal Tregs as a unique population,” commented Jonathan Kipnis of Washington University, St Louis.
“These findings extend our understanding of tissue-resident Tregs as critical regulators of neuroimmune crosstalk, with significant implications for neuroinflammatory and neurodegenerative diseases,” commented Patrick Rodrigues and Marco Colonna, also of Washington University. “Targeting meningeal Tregs could open new avenues for interventions in conditions such as multiple sclerosis, neurodegeneration, and cognitive decline.”
To Costantino Iadecola of Weill Cornell Medical College in New York, the results cast meningeal T-regs, despite being so few, as important regulators of immune homeostasis within the meninges. More broadly, it demonstrates that alteration of this delicate immune balance in the meninges has a powerful influence on the brain as a whole, he said.
In recent years, scientists have exposed the meningeal layers surrounding the brain as a bustling hub of immune cells, whose composition and activation states change with age, and with disease (Oct 2019 news; May 2021 news). In models of aging and AD, scientists have found that T cells, in particular, appear to inflict damage when they infiltrate the brain (Jan 2020 news; Dec 2022 news; Mar 2023 news). How might Tregs fit in? Do they suppress harmful immune responses in the brain, as they do in other tissues?
First author Miguel Marin-Rodero and colleagues decided to find out. Specifically, they wanted to identify and characterize Tregs that populate the meninges under healthy conditions. First, they used flow cytometry to hunt for cells within the dura mater expressing the telltale combination of Treg markers—CD4 and FoxP3. At just 125 cells per mouse, the dural Treg population was tiny but unmistakable. This scarcity is par for the course for Tregs, which exist in slightly smaller proportions in the spleen. The dural Tregs were more than a full order of magnitude more plentiful than their counterparts inhabiting the two innermost meninges and the choroid plexus, where less than 10 cells per mouse could be found in each of these regions. Tregs also exist within the brain parenchyma, but are exceedingly rare under healthy conditions.
Focusing on the dura mater, the scientists used green fluorescent protein-tagged FoxP3 to spot these cells, detecting most congregating around veins, aka sinuses, that transect this outermost layer of the meninges (image below).
Some Tregs were dispersed, while others huddled in clusters with other T cells along with antigen presenting cells such as dendritic cells. Notably, meningeal Tregs increased in number as mice aged.
Calming Influence. Tregs (green) cluster with other immune cells, including MHC II+ antigen presenting cells (blue) and other T cells (pink) along dural sinuses. [Courtesy of Marin-Rodero et al., Science Immunology, 2025.]
The scientists characterized the meningeal Tregs with single-cell transcriptomics. While the cells expressed markers shared by Tregs stationed in other parts of the body, they also had their own distinct signature. For example, they expressed genes known to promote or prevent neuronal death, such as Ifng, Il10, Cd200r, Wisp, and Ptgs1. Marin-Rodero also found that 5.5 percent of the Tregs they examined shared the exact same T cell receptor sequence with at least one other cell, suggesting they had clonally expanded in response to antigens. Mathis said she does not know what those antigens are.
To find out what the meningeal Tregs are up to, the researchers got rid of them using a transgenic mouse expressing the diphtheria toxin receptor under control of the Treg-specific FoxP3 promoter. Treating these mice with diphtheria toxin removed most T-regs in the meninges. This toxin cannot cross into the brain, leaving the scant T-regs residing within the parenchyma unaffected.
Left to their own devices, it didn’t take long before the other immune cells in the meninges started acting up in these transgenics. Three days after the Tregs were gone, CD4+ and CD8+ T cells, representing helper and cytotoxic varieties, respectively, had expanded within the meninges, and revved up expression of IFN-γ. Myeloid cells in the meninges cranked up MHC II.
This finding dovetails with recent work from Kipnis’ lab on self-peptides presented by MHCII on meningeal macrophages driving suppression of autoreactive T cells there (Kim et al., 2025).
How would this immune awakening influence the brain? For one, it opened the floodgates for T and natural killer (NK) cells to infiltrate the parenchyma, where they scattered across the hippocampus and, to a lesser extent, the cingulate cortex. More so than any other brain region, the hippocampus was awash with IFN-γ.
Reactivity, Unleashed. Astrocytes in the hippocampus exist in four transcriptional states (left). Depletion of Tregs (middle) shifted the population toward a reactive state (right). [Courtesy of Marin-Rodero et al., Science Immunology, 2025.]
Astrocytes, oligodendrocytes, and microglia in the hippocampus all reacted (image above). Under the confocal microscope, both astrocytes and microglia within dentate gyrus sections retracted their processes, assuming an activated stance—all in response to removal of about 125 Tregs from the meninges.
Mad Microglia. With Tregs in the meninges, microglia in the hippocampus project processes (left). When Tregs are depleted, microglia retract their branches and round up (right). [Courtesy of Marin-Rodero et al., Science Immunology, 2025.]
The scientists don’t know how and why the T cells infiltrated the hippocampus. They confirmed that the blood-brain border remained largely intact, suggesting the cells did not wander in from the circulation. In T-reg-depleted mice, the researchers spotted hordes of T cells in the double-layered invagination of the pia mater positioned just under the hippocampus. Called the velum interpositum, this region is a hotspot of immunocyte trafficking during inflammation, and Mathis thinks it might funnel activated T cells into the hippocampus.
Did the hippocampus suffer consequences? It sure did. For one, the inflammation hurt neurogenesis. The region’s dentate gyrus is one of only two places where new neurons are born in the adult brain, and the scientists found that this was compromised by the loss of meningeal Tregs. They found a dearth of pluripotent progenitors in the dentate gyrus. Called radial-glia-like cells, they give rise to neuronal progenitors that ultimately differentiate into new neurons. Further experiments revealed that radial-glial-like cells, which express IFN-γ receptors, were dying due to IFN-γ spewed by activated T and NK cells. IFN-γ-blocking antibodies prevented this death. The scientists also found that mice were less able to discriminate between familiar and unfamiliar arms of a Y-maze, suggesting they had short-term-memory loss in this hippocampal task. This deficit persisted at least eight weeks after Treg depletion.
Finally, Marin-Rodero investigated how Tregs manage to keep the cadre of other immune cells in check. They found that, as in other tissues, Tregs, which express a high-affinity receptor for IL-2, outcompete other T cells and NK cells for this crucial growth factor. Blocking IL-2 prevented the meningeal immune flare-up and all of its detrimental consequences in response to Treg depletion. Conversely, antibodies that activate the lower-affinity IL-2 receptors on conventional T cells and NK cells caused many of the same problems as depleting Tregs. Agonizing the Treg IL-2 receptor expanded these protective cells instead.
Mathis noted striking parallels between what happens in response to Treg removal, and what occurs in aging and in neurodegenerative disease, including AD and PD. Namely, IFN-γ -producing T cells invade and damage in the brain. She proposed that in the face of growing inflammatory responses to age-related scourges such as amyloid, neurofibrillary tangles, Lewy bodies, and similar aggregates, Tregs might become overwhelmed and fail to restrain their increasingly riled T cell cousins. Her lab is investigating further in mouse models of AD in collaboration with David Holtzman’s group at Washington University in St. Louis, and separately in human tissue samples.
To Holtzman’s mind, the results speak to the importance of Tregs in the meninges. “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,” he wrote. “This work opens the stage for many exciting future studies.”—Jessica Shugart
References
News Citations
- Do Immune Cells in the Meninges Help with … Memory?
- As Mice Age, T Cells Traipse Around Their Meninges. Mayhem Ensues
- Attack of the Clones? Memory CD8+ T Cells Stalk the AD, PD Brain
- In AD, CSF Immune Cells Hint at Mounting Mayhem in the Brain
- Neurodegeneration—It’s Not the Tangles, It’s the T Cells
Paper Citations
- 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.
Further Reading
No Available Further Reading
Primary Papers
- 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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Comments
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.
Washington University School of Medicine
Washington 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.
Washington 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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