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MAIT cell deficiency exacerbates neuroinflammation in P301S human tau transgenic mice

Journal of Neuroinflammation volume 22, Article number: 90 (2025) Cite this article

Abstract

Background

The role of immune cells in neurodegeneration remains incompletely understood. Accumulation of misfolded tau proteins is a hallmark of neurodegenerative diseases. Our recent study revealed the presence of mucosal-associated invariant T (MAIT) cells in the meninges, where they express antioxidant molecules to maintain meningeal barrier integrity. However, the role of MAIT cells in tau-related neuroinflammation and neurodegeneration remains unknown.

Methods

Flow cytometry analysis was performed to examine MAIT cells in human Tau P301S transgenic mice. Tau pathology, hippocampus atrophy, meningeal integrity, and microglial gene expression were examined in Mr1−/− P301S mice that lacked MAIT cells and control P301S transgenic mice, as well as Mr1−/− P301S mice with adoptive transfer of MAIT cells.

Results

The meninges of P301S mutant human tau transgenic mice had increased numbers of MAIT cells, which retained their expression of antioxidant molecules. Mr1−/−P301S mice that lacked MAIT cells exhibited increased tau pathology and hippocampus atrophy compared to control Mr1+/+P301S mice. Adoptive transfer of MAIT cells reduced tau pathology and hippocampus atrophy in Mr1−/− P301S mice. Meningeal barrier integrity was compromised in Mr1−/−P301S mice, but not in control Mr1+/+P301S mice. A distinctive microglia subset with a proinflammatory gene expression profile (M-inflammatory) was enriched in the hippocampus of Mr1−/−P301S mice. The transcriptomes of the remaining microglia in these mice also shifted towards a proinflammatory state, with increased expression of inflammatory cytokines, chemokines, and genes related to ribosome biogenesis and immune responses to toxic substances. The transfer of MAIT cells restored meningeal barrier integrity and suppressed microglial inflammation in the Mr1−/− P301S mice.

Conclusions

Our data indicate an important role for MAIT cells in regulating tau-pathology-related neuroinflammation and neurodegeneration.

Background

Aberrant aggregation of misfolded microtubule-associated protein tau is a prominent feature of neurodegenerative disorders [1]. Previous studies have shown that the density of neurofibrillary tangles, which are intracellular aggregates of hyperphosphorylated tau, correlates with the severity of cognitive decline in Alzheimer's disease patients [2, 3]. Recent research suggested a complex interplay between tau pathology and neuroinflammation. Notably, microglial inflammation has been observed in mice carrying human tau mutants associated with degenerative tau pathologies, suggesting that tau-induced pathologies can trigger neuroinflammation [4]. Conversely, reactive microglia and its products may also exacerbate tau pathology and associated neurodegeneration [5,6,7,8].

Moreover, recent studies suggest that non-microglial immune cells, such as lymphocytes, may play a role in modulating tau pathology-related neuroinflammation and neurodegeneration [5]. CD8+ T cells infiltrate the brain parenchyma in Alzheimer's disease patients, as well as in 3D human neuroimmune culture derived from stem cells from AD patients and in mouse models with tauopathy [5, 9,10,11,12]. Increased infiltration of CD8+ T cells into 3-D human neuroimmune culture led to increased microglial activation, neuroinflammation and neurodegeneration [9]. Depletion of CD8+ T cells has also been shown to reduce tau pathology and prevent tau-mediated neurodegeneration in mouse models [5]. However, the roles of other lymphocyte subsets in regulating tau pathology and neurodegeneration remain largely unexplored.

The brain parenchyma is protected by complicated barrier structures, including blood brain barriers (BBB), choroid plexus, and meninges [13, 14]. Various immune cells are enriched in these brain barrier regions. We recently found that MAIT cells, a subset of microbiota-responsive innate-like T cells, were present in the leptomeninges and secreted many antioxidant proteins to protect meningeal barrier integrity [15]. MAIT cell-deficient mice exhibited notable meningeal barrier leakage, which inflamed the brain and disrupted cognitive function [15]. These data together demonstrate an important role for MAIT cells in protecting meningeal barrier integrity, and suggest that active maintenance of the meningeal barrier integrity by tissue-resident immune cells is essential for restricting neuroinflammation and for protecting cognitive function. However, whether this barrier-protective function influences tau-mediated neuroinflammation and neurodegeneration remains unknown.

In this study, we crossed MAIT cell-deficient mice (Mr1−/−) with P301S mutant human tau transgenic mice to investigate the potential roles of MAIT cells in regulating tau pathology, neuroinflammation, and neurodegeneration. We found that MAIT cells are present in the meninges of P301S mice and maintain high expression of antioxidant molecules. Our results indicate that the absence of MAIT cells leads to meningeal leakage, increased neuroinflammation, and exacerbated tau pathology and hippocampal atrophy in P301S transgenic mice. These findings suggest that MAIT cells play a role in modulating tau pathology and associated neuroinflammation and neurodegeneration.

Methods

Animals

P301S mice [4] and control mice on mixed C57BL/6 and C3H background were obtained from JAX laboratory. Mr1−/− mice on C57BL/6N background were described previously [15, 16]. Mr1−/− mice were generated by Taconic, and the validation and characterization of these mice were in the supplementary files of our previous publication [16]. P301S mice were bred with Mr1−/− mice at the animal facility of Rutgers University. The offsprings were bred with each other and used in this study. Age and sex-matched female and male mice of 7 to 8-month-old were used. All animal experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee at Rutgers University.

Age and sex-matched mice were randomly assigned to experimental and treatment groups. Experimenters were not blinded to the experimental groups. Mice with signs of major stress or sickness such as paralysis or notable reduction in food uptake were euthanized and excluded from the study. However, such incidents were rare in mice bred in our animal facility at the ages of this study. Except for snRNA-seq, at least two independent experiments were performed for each experiment. For immunofluorescence staining, imaging, and weight measurements, mice of the desired ages were euthanized on different dates, with staining or other measurements performed at the same time for each experiment. For flow cytometry analysis, mice with a birthdate difference of less than 7 days were euthanized at the same time for each independent experiment. For snRNA-seq, mice with a birthdate difference of less than 3 days were euthanized at the same time.

Flow cytometric analysis and fluorescence activated cell sorting (FACS)

Flow cytometric analysis and FACS sorting of MAIT cells were carried out as previously described [15]. Briefly, the meninges were carefully isolated from the outer dorsal cerebrum and inner calvaria surface. Hippocampus and cortex tissue were dissected on ice. The tissue was incubated for 20 min at 37 °C in HBSS containing 0.2 mg/mL Liberase TM and 0.1 mg/mL DNase I to facilitate digestion. For analysis of meningeal cells, the digested tissue was passed through a 70 µm cell strainer to generate a single-cell suspension. For analysis of hippocampus and cortex immune cells, Percoll centrifugation was performed to remove the debris, following enzymatic digestion. For flow cytometry, the cells were stained with MR1 tetramers along with antibodies targeting surface antigens for 30 min at 22 °C. The mouse MR1 5-OP-RU tetramers were obtained from the NIH Tetramer Core Facility. The MR1 tetramers were produced by the NIH Tetramer Core, as authorized for distribution by the University of Melbourne [17]. To define and characterize MAIT cells, surface markers used in the analysis included anti-TCRβ (H57-597), anti-CD3ε (145-2C11), anti-B220 (RA3-6B2), anti-NK1.1 (PK136), anti-CD11b (M1/70), anti-CD45 (104), anti-IL18R (A17071D), anti-Thy1.2 (53–2.1), and anti-IL7R (A7R34). Anti-B220, anti-NK1.1, and anti-CD11b antibodies were used to exclude B cells, NK cells, and myeloid cells to enhance MAIT cell identification. These antibodies were obtained from Biolegend, Thermo, or BD Biosciences. In flow cytometry and FACS sorting for QPCR analysis, meningeal MAIT cells were identified as CD45+ CD11b− B220− NK1.1−Thy1+ MR1tetramer+ CD3/TCRβ+, as we previously described [15, 16]. In some experiments, anti-IL18R and anti-IL7R antibodies were used for further characterize MAIT cells. Dead cells were excluded using DAPI (Thermo). For adoptive transfer experiments, no anti-CD3 or anti-TCRβ antibodies were included to prevent cell activation, and donor MAIT cells were identified as CD45+ Thy1+ IL-18R+ MR1tetramer+.

For analysis and sorting of hippocampal microglia, hippocampal tissue was processed using the papain-based Pierce™ Primary Neuron Isolation Kit (Thermo), according to the manufacturer’s protocol. The cells were passed through a 70 µm cell strainer and stained with surface markers, including anti-CD11b (M1/70) and anti-CD45 (104), before being sorted by FACS. Microglia was identified as CD11bmed/lowCD45med/low cells as we previously described [18,19,20]. In some experiments, anti-CD68 (FA-11), anti-CD86 (GL-1), anti-F4/80 (BM8), anti-MHCII (M5/114.15.2), and anti-CD11c (N418) were used to characterize microglia. Intracellular cytokine staining was performed as we previously described [16, 18,19,20,21,22,23]. Specifically, after digestion, cells were cultured with serum free RPMI medium for 4 h, and 1 µM monensin was added for the last 2 h. The cells were then stained for surface markers to identify microglia, followed by intracellular staining with anti-TNF antibody (MP6-XT22). Intracellular cytokine staining was performed using the Cytofix/Cytoperm Kit (BD) as per the manufacturer’s instructions.

Flow cytometry was performed using a 4-laser LSRII (BD Biosciences) or a 4-laser Cytek Aurora, and cell sorting was performed on a Cytek Aurora CS cell sorter.

Immunofluorescence staining

For immunofluorescence staining, mice were first perfused with 50 mL of PBS, followed by 50 mL of 4% paraformaldehyde. The brains were fixed overnight in 4% paraformaldehyde at 4 °C and then placed in 30% sucrose at 4 °C until the tissue sank. The brains were then embedded in OCT and stored at −80 °C. The brain sections were cut at 40 µm using a CM1850 cryostat (Leica). The sections were stained with AT8 (Thermo) or anti-IBA1 (Fujifilm Wako) primary antibodies overnight at 4 °C, followed by labeling with AF594-conjugated donkey anti-mouse IgG (Thermo) or AF647-conjugated goat anti-rabbit IgG (Thermo) secondary antibodies. AT8 antibodies (Thermo Fisher) were used at a dilution of 1:100. Anti-IBA1 antibodies were used at a dilution of 1:1000. Images of the slides were captured using a BZ-X800 all-in-one fluorescence microscope (Keyence) with the BZ-X800 software. Images were analyzed by ImageJ.

Examination of hippocampus weight and volume

For measurement of the hippocampus weight, the hippocampal tissue was carefully isolated from each hemisphere and weighed in an EP tube. The weight was calculated by subtracting the weight of the tube before and after adding the hippocampal tissue. For hippocampus volume measurements, 40 µm brain sections were cut sequentially and divided into four sets, with each set corresponding to one of the four consecutive cuts. One set of sections was used for hippocampus volume measurement. Sections were mounted with mounting medium containing DAPI and scanned by the Keyence microscope. Hippocampus volumes were calculated as total hippocampus areas of the sections × 0.04 mm × 4.

Adoptive transfer of MAIT cells

For adoptive transfer, meningeal MAIT cells (CD45+Thy1+IL18RhiMR1-tetramer+) from 7-month-old P301S mice were sorted by FACS, and 1000 cells were transferred to 6 weeks old Mr1−/− P301S mice intravenously. To minimize undesired cell activation, CD3 and TCR antibodies were not included for purification of donor cells for adoptive transfer. Centrifugation, FACS sorting and preparation for adoptive transfer, were carefully performed on ice or 4 °C. Meningeal leakage assays, immunofluorescence assays and hippocampus weight measurement were performed when recipient mice were around 7–8 months old.

Transcranial SR101 assay

Transcranial SR101 assays were performed as we previously described. For transcranial SR101 assay, mice were anesthetized with Ketamine and Xylazine. The skulls were exposed, and a light 4 mm diameter rubber ring was placed around the bregma. SR101 (2.5 mM in 15 µl artificial CSF) was dropped into the rubber ring on top of the bregma, and was periodically replenished to prevent drying. At 20 min after SR101 administration, the skull was washed with artificial CSF. Mice were quickly euthanized and brain tissue was immediately obtained. 300 µM coronal brain sections were quickly cut with a vibratome. Sections at 300 µM—600 µM away from the bregma were rapidly mounted on slides with a chamber filling with pre-chilled DAPI, and immediately imaged by Zeiss Axio Observer fluorescence. The Zeiss Zen 3.1 software (Zeiss) software was used to process the images. To quantify SR101 intensity, a 50 × 100 µM BOX was drawn at 50 µM beneath the meninges, and the mean fluorescence intensity value was obtained.

Single nucleus RNA-seq

For single nucleus RNA-seq (snRNA-seq), the hippocampus was quickly isolated from fresh mouse brains on ice, and placed in Hibernate E medium (Gibco) supplemented with B27 (GibcO) and 1% GlutaMAX (Gibco). The tissue was homogenized using a Dounce grinder in pre-cooled RNase-free lysis buffer (10 mM Tris–HCl, 10 mM NaCl, 3 mM MgCl2, 0.1% NonidetTM P40). The homogenization was performed with 15 strokes using a loose pestle, followed by 7 strokes using a tight pestle. The tissue was then lysed on ice for 15 min, and the solution was filtered through a 30 µm cell strainer. The nuclei were washed, and myelin was removed using myelin removal kit (Miltenyi) according to the manufacturer’s instructions. Libraries were prepared using 3’ GEM gene expression kit (10xgenomics) following the manufacturer’s instructions. Libraries were sequenced using a Novaseq. The scRNA-seq data were analyzed using the R package Seurat 4.3.0. Nuclei with fewer than 200 but more than 6500 genes, or more than 5% of mitochondrial genes, were filtered out. The R package DoubletFinder 2.0.3 was used to remove the doublets. Normalization of the data was achieved using the SCTransform function within Seurat. Cell clustering was performed using Uniform Manifold Approximation and Projection (UMAP). Microglia/macrophage population was sorted in silicon based on expression of positive markers of myeloid immune cells (e.g. Itgam, Ptprc) and the absence of markers associated with other immune cells (e.g. T/B/NK/ILC cells, monocytes, granulocytes). The microglia/macrophage population was then separated into distinct microglia subsets using UMAP. Gene markers for each microglia subset and differentially expressed genes between microglia subsets of Mr1−/− P301S and control Mr1+/+ P301S mice were identified using a threshold of false discovery rate of < 0.05. The Gene Set Enrichment Analysis (GSEA) algorithm was utilized to access the enriched gene sets from differential genes. In brief, the differential gene expression of targeted groups was calculated with the R package limma 3.56.2. Then the differential genes were preranked by log2FoldChange and subjected to the R package clusterProfiler 4.8.3. Results with p value < 0.05, NES > 1 and False discovery rate < 0.25 were considered significant for GSEA analysis.

Multiplex cytokine assays and QPCR analysis

Multiplex cytokine assays were performed as we previous described [18, 20]. The brain was homogenized with 1 ml of PBS containing protease inhibitors using a tissue homogenizer. Concentrations of proinflammatory cytokines in brain homogenates were measured using LegendPlex kits, a kit for bead-based multiplex assays (Biolegend) [24], following the manufacturer’s instructions.

For QPCR analysis, cells were sorted by FACS. cDNA was made by mRNA extraction and reverse transcription, or using a Cells-to-CT kit (Thermo). For mRNA extraction, mRNA was extracted using the RNeasy Plus Mini Kit (Qiagen), following the manufacturer's protocols. Complementary DNA (cDNA) was synthesized using SuperScript II Reverse Transcriptase (Thermo). For the Cells-to CT method, cDNA was generated using the Cells-to-CT kit (Thermo). qPCR was carried out using ABI pre-optimized TaqMan probes (Thermo).

Statistical analysis

For snRNA-seq data, Wilcoxon rank-sum test was used to determine significance of differentially expressed genes. False discovery rate less than 0.05 was considered significant. A Mann–Whitney U test was used to compare the differences in the percentages of subsets in each mouse for snRNA-seq data, and a p-value of less than 0.05 was considered significant. For GSEA analysis, results with p value < 0.05, NES > 1 and False discovery rate < 0.25 were considered significant. For other experiments, student T test, or ANOVA test with Tukey’s post-hoc test was used to determine the difference between two groups. A p-value of less than 0.05 was considered significant.

Results

MAIT cells are present in the meninges of P301S mutant human tau transgenic mice and retain expression of antioxidant molecules

Our recent work indicates that MAIT cells are present in adult mouse meninges where they secrete antioxidant molecules to protect meningeal barrier integrity [15]. We performed flow cytometry analysis to examine MAIT cells in the meninges and brain parenchyma regions of P301S mutant human tau transgenic mice to determine whether tau pathology might affect MAIT cells abundance and distribution. MAIT cells were detected in the meninges of 7-month-old P301S mice, and their numbers were increased compared to age-matched control wildtype mice (Fig. 1A, B, Fig. S1). We did not observe significant infiltration of MAIT cells into the brain parenchymal regions such as hippocampus and cortex of P301S mice (Fig. 1B, C). Meningeal MAIT cells in 7-month-old wildtype mice expressed MAIT-characteristic markers such as IL7R, IL18R, and CD3e, verifying their identity (Fig. 1D). They expressed comparable mRNA levels of antioxidant molecules such as Selenop, Selenof, Fth1, Tmsb4x, and Psap, as MAIT cells in wildtype mice, indicating that MAIT cells in P301S mice might retain antioxidant activities (Fig. 1E). Thus, MAIT cells are increased in the meninges of P301S mice and retain expression of antioxidant molecules.

Fig. 1
figure 1

MAIT cells are present in meninges of P301S mice and retain expression of antioxidant molecules. A Representative flow cytometry profiles of MAIT cells in the meninges of 7-month-old P301S mice and control wildtype mice. Plots were pre-gated on CD45+CD11b−B220−Thy1+ cells. B Numbers of MAIT cells in the meninges, hippocampus (HP), and cortex of 7-month-old P301S mice and wildtype mice. C Representative flow cytometry profiles of MAIT cells in the hippocampus and cortex. D Representative flow cytometry profiles showing expression of the indicated proteins by meningeal MAIT cells in P301S mice. Plots were pre-gated on meningeal MAIT cells in P301S mice. E mRNA levels of the indicated genes in meningeal MAIT cells of 7-month-old P301S mice and control wildtype mice. Data are from 6 mice per group pooled from 2 independent experiments B, or 4 independent experiments with 5 mice per group pooled per experiment E. Data were normalized to Gapdh. Error bars = mean ± SEM. **p < 0.01. Sex information in Additional file 1

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MAIT cell deficiency exacerbates tau pathology and hippocampus atrophy in P301S mice

Because MAIT cell development requires Mr1-expressing thymocytes for positive selection, Mr1−/− mice lack MAIT cells due to failure in early development [25]. To examine the potential role of MAIT cells in regulating tau pathology, we crossed Mr1−/− mice, which lacked MAIT cells, with P301S mice. As expected, MAIT cells were absent in the meninges of Mr1−/− P301S mice (Fig. 2A, B). We examined tau pathology by immunofluorescence staining with AT8 antibody, which detects tau phosphorylation at the Ser202 and Thr205 positions [26, 27]. In mice bred in our animal facility, Mr1−/− P301S mice exhibited significantly increased p-tau pathology compared to control Mr1+/+P301S mice as early as 7 months old (Fig. 2C, D). At 8 months old, Mr1−/− P301S mice showed a drastic increase in p-tau pathology compared with control Mr1+/+P301S mice (Fig. 2E, F). These data suggest that MAIT cell deficiency might exacerbate tau pathology.

Fig. 2
figure 2

MAIT cells repress tau pathology and neurodegeneration in P301S mice. A Representative flow cytometry profiles of MAIT cells in the meninges of 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. Plots were pre-gated on CD45+CD11b−B220−Thy1+ cells. B Numbers of MAIT cells in the meninges of 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. C Immunofluorescence staining of p-Tau (antibody clone AT8) in the hippocampus DG of 7-month Mr1−/− P301S mice and control Mr1+/+ P301S mice. D Percentages of AT8 + areas in the hippocampus DG of 7-month Mr1−/− P301S mice and control Mr1+/+ P301S mice. E Immunofluorescence staining of p-Tau (antibody clone AT8) in the hippocampus DG of 8-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. F Percentages of AT8 + areas in the hippocampus of 8-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. G Representative images of hippocampus of 7.5-month Mr1−/− P301S mice and control Mr1+/+ P301S mice. H Weight of the hippocampus in 7.5-month Mr1−/− P301S mice and control Mr1+/+ P301S mice. I Volumes of the hippocampus in 7.5-month Mr1−/− P301S mice and control Mr1+/+ P301S mice. J MAIT cells were transferred to 6-week-old Mr1−/− P301S mice. Number of MAIT cells in meninges of recipient mice was measured by flow cytometry analysis, when the mice were 8-months old. K mRNA levels of Selenop in MAIT cells purified from 8-month-old Mr1−/− P301S mice with adoptive transfer of MAIT cells, and control MAIT cells purified from 8-month-old Mr1+/+ P301S mice without adoptive transfer. L Immunofluorescence staining of p-Tau (antibody clone AT8) in the hippocampus DG of 8-month Mr1−/− P301S mice with adoptive transfer of MAIT cells or PBS. M Percentages of AT8 + areas in the hippocampus DG of 8-month Mr1−/− P301S mice with adoptive transfer of MAIT cells or PBS. N Representative images of hippocampus of 7.5-month Mr1−/− P301S mice with adoptive transfer of MAIT cells or PBS. O Weight of the hippocampus in 7.5-month-old Mr1−/− P301S mice with adoptive transfer of MAIT cells or PBS. P The volumes of hippocampus in 7.5-month-old Mr1−/− P301S mice with adoptive transfer of MAIT cells or PBS. Data are from 6 mice per group pooled from 2 independent experiments (B, J, K), or are from 8 mice per group representative of two independent experiments (D, F, M), or are from 10 mice per group pooled from more than two independent experiments (H, I, O, P). Error bars = mean ± SEM. **p < 0.01; *p < 0.01. Sex information in Additional file 1

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We noted that 7-month-old P301S mice directly purchased from JAX had higher levels of tau pathology compared to 7-month-old Mr1+/+P301S mice bred in our institutional animal facility (Fig. S2). This might be due to genetic factors related to crossing, or environmental factors such as microbiota or nutrients or chronic exposure to environmental stimuli or stress. As expected, Mr1−/− mice without human tau mutant transgenes did not exhibit significant AT8 staining in their hippocampus (Fig. S3A).

At 7.5 months of age, most control Mr1+/+P301S mice did not yet exhibit notable hippocampus atrophy in mice bred in our animal facility (Fig. 2, G–I). In contrast, Mr1−/− P301S mice displayed significant hippocampus atrophy at this age, indicating that the absence of MAIT cells may exacerbate tau-related neurodegeneration (Fig. 2, G–I). Of note, Mr1−/− mice without human tau mutant transgene did not show hippocampus atrophy, suggesting that the increased neurodegeneration in Mr1−/− P301S mice was associated with tau pathology (Fig. S3B, S3C). Together, these data indicate that MAIT cell deficiency may exacerbate neurodegeneration in P301S mice.

We next performed MAIT cell adoptive transfer experiments to verify the role of MAIT cells in regulating tau pathology and neurodegeneration (Fig. S4A). Adoptive transfer of MAIT cells partially restored MAIT cell numbers in the meninges (Fig. 2J, Fig. S4B). The adoptive transfer efficiency is around 30% to 50%. QPCR analyses revealed that the MAIT cells transferred into Mr1−/− P301S mice expressed higher levels of the antioxidant molecule genes Selenop and Fth1 compared to control MAIT cells from Mr1+/+P301S mice (Fig. 2K, Fig. S4C). These data were consistent with our previous finding that reduced TCR exposure is associated with increased expression of antioxidant molecules in MAIT cells [15]. MAIT cell transfer significantly repressed p-tau pathology and hippocampus atrophy in Mr1−/− P301S mice (Fig. 2, L-P). Together, these data indicate that MAIT cells repress tau pathology and neurodegeneration in adult P301S mice.

MAIT cell deficiency leads to meningeal leakage and increased microglial inflammation in P301S mice

We aim to understand the mechanisms by which MAIT cells suppress tau pathology and neurodegeneration in P301S mice. Previous studies indicate that increased microglial inflammation can exacerbate tau pathology and neurodegeneration in P301S mice [5, 28,29,30]. Our previous work suggests that MAIT cells protect meningeal barrier integrity via secretion of antioxidant molecules [15], which could help prevent noxious substances from entering the brain parenchyma and triggering enhanced microglial inflammation. We thus examined meningeal barrier integrity and microglial activities in Mr1−/− P301S mice. At 7-months of age, a remarkable leakage in the meningeal barrier was observed in 7-month-old Mr1−/− P301S mice, but not in control Mr1+/+ P301S mice (Fig. 3A, B). Immunofluorescence staining assays revealed markedly increased Iba1 reactivity in the hippocampus of Mr1−/− P301S mice compared to Mr1+/+ P301S mice, indicating microglial/macrophage dysfunction (Fig. 3C, D). Flow cytometry analysis showed that microglia from the hippocampus Mr1−/− P301S mice exhibited elevated expression of the proinflammatory cytokine TNF (Fig. 3E–G). Hippocampal microglia in Mr1−/− P301S mice had increased expression of CD68 and F4/80, while expression of CD86, CD11b, MHCII, and CD11c remained unchanged (Fig. 3H, 3I, Supplementary S5). These data suggest that MAIT cell deficiency may increased microglia/macrophage inflammation in P301S mice.

Fig. 3
figure 3

MAIT cells protect meningeal barrier integrity and repress proinflammatory cytokine expression from microglia. A Brain vibratome sections were obtained from 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice with transcranial administration of SR101. Representative imaging of sections at 300 µM to 600 µM lateral to bregma. B Quantification of fluorescence intensity of SR101 at 50 µM below the leptomeningeal cells in the brain vibratome sections of 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. C Immunofluorescence staining of IBA1 in hippocampus DG of 7-month Mr1−/− P301S mice and control Mr1+/+ P301S mice. D Percentages of IBA1 + areas in the hippocampus DG of 7-month Mr1−/− P301S mice and control Mr1+/+ P301S mice. E Representative flow cytometry profile showing gating strategy of microglia in the hippocampus. F Representative flow cytometry profiles showing expression of TNF in microglia in the hippocampus of 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. G Mean fluorescence intensity of TNF in microglia in the hippocampus of 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. H Representative flow cytometry profiles showing expression of the indicated molecules by hippocampus microglia in 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. I Mean fluorescence intensity of the indicated molecules in microglia in the hippocampus of 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. J MAIT cells were transferred to 6-week-old Mr1−/− P301S mice. Bain vibratome sections were obtained in mice with transcranial administration of SR101, when mice were 7-month-old. Representative images for mice with adoptive transfer of MAIT cells or PBS control. K Quantification of fluorescence intensity of SR101 at 50 µM below the leptomeningeal cells in mice with adoptive transfer of MAIT cells or PBS control. L Immunofluorescence staining of IBA1 in the hippocampus DG of 7-month-old Mr1−/− P301S mice with adoptive transfer of MAIT cells or PBS. M Percentages of IBA1 + areas in the hippocampus of 7-month-old Mr1−/− P301S mice with adoptive transfer of MAIT cells or PBS. N Representative flow cytometry profiles showing expression of TNF in microglia in the hippocampus of 7-month-old Mr1−/− P301S mice with adoptive transfer of MAIT cells or PBS. O Mean fluorescence intensity of TNF in the hippocampus of 7-month Mr1−/− P301S mice with adoptive transfer of MAIT cells or PBS. Data are from 4–6 mice per group, representative of 2 independent experiments. Error bars = mean ± SEM. **p < 0.01, *p < 0.05. Sex information in Additional file 1

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Transfer of MAIT cells restored meningeal integrity in Mr1−/− P301S mice, indicating that MAIT cells help prevent meningeal leakage in P301S mice (Fig. 3J, K). MAIT cell transfer reduced IBA1 reactivity in the hippocampus of Mr1−/−P301S mice (Fig. 3L, M). and decreased the expression of TNF (Fig. 3N, O). These results indicate that the absence of MAIT cells leads to meningeal leakage and increased microglia inflammation in Mr1−/− P301S mice.

Characterization of the transcriptomes of microglia in Mr1 −/− P301S mice

We next performed single-nucleus RNA-seq to examine the transcriptomes of microglia in the hippocampus of Mr1−/− P301S mice and control Mr1+/+P301S mice. Unsupervised UMAP divided hippocampal microglia/macrophage cells into several subsets (Fig. 4A, Additional File 2). All subsets expressed high levels of the immune-cell specific gene Ptprc (encoding CD45) and microglia/macrophage gene markers Itgam (encoding CD11b), Adgre1 (encoding F4/80), and Trem2 (Fig. S6). A subset expressed both microglia/macrophage and also neuron genes such as Nrg3, Dlg2, Drxn3 (Fig. S6). These transcriptomes are possibly doublets, and are therefore not included in further analysis (Fig. S6). The three most abundant microglia subsets differed in their expression of ribosome biogenesis genes encoding ribosome proteins, and were thus termed “M_ribo_hi”, “M_ribo_med”, and “M_ribo_lo” (Fig. 4A, B). In addition, a few minor subsets were detected (Fig. 4A). M_proliferating expressed high levels of proliferation markets such as Ki67 (Fig. 4B). M_ISG expressed high levels of interferon stimulated genes (ISG) such as Ifi44, Oasl2, Ifit2, Ifi204, and Ifit3. M_magi2 was named by their expression of characteristic genes Magi2, but lacked significant expression of other non-microglia genes (Fig. 4B, Fig. S6, Additional file 2). Notably, a distinct subset of microglia appeared, expressing a high level of proinflammatory cytokines such as Tnf, Il1a, and Il1b, as well as proinflammatory chemokines such as Ccl3 and Ccl4 (Fig. 4A, B). We named this subset Inflammatory Microglia (M_inflammatory) (Fig. 4A, B). Mr1−/− P301S mice had significantly higher percentages of M_inflammatory subset, compared to control Mr1+/+ P301S mice (Fig. 4C, D). The other microglia/macrophage subsets did not show significant difference in percentages between Mr1−/− P301S mice and control Mr1+/+ P301S mice (Fig. 4C, D). Thus, Mr1−/− P301S mice had accumulation of a distinctive subset of microglia expressing high levels of proinflammatory genes.

Fig. 4
figure 4

Transcriptome profiles of hippocampus microglia in 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice A UMAP plot showing different clusters of microglia/macrophage in the hippocampus of 7-month-old mice by single-nucleus RNA-seq analysis. Shown are all microglia/macrophage pooled from four 7-month-old Mr1−/− P301S mice and four control Mr1+/+ P301S mice. B Dot plots showing expressional levels of the indicated genes of each subset. C Percentages of each microglia and macrophage subset. D UMAP plots showing different clusters of microglia/macrophage in the hippocampus of 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice separately. E Enrichment of the indicated gene sets in M_inflammatory cells versus the other microglia/macrophage subsets. F Volcano plots depict genes that are significantly upregulated or downregulated in M_inflammatory cells compared to other microglia/macrophage cells. G Dot plots showing expressional levels of the indicated genes of each subset. Data are from 4 mice per group. Sex information in Additional file 1. Error bars = mean ± SEM. *p < 0.05. Sex information in Additional file 1

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We performed a more thorough analysis of M_inflammatory cells. GSEA analysis revealed that these cells exhibit higher expression of genes associated with proinflammatory cytokine and chemokine pathways, as well as immune and inflammatory responses to toxic substances (Fig. 4E). Notably, the proinflammatory cytokine and chemokine genes Tnf, Il1b, Ccl3, and Ccl4 were among the most significantly upregulated in M_inflammatory cells (Fig. 4F). In addition to these proinflammatory mediators, these cells showed elevated expression of other genes related to responses to toxic substances (e.g. Slc2a1, Mapkapk2, Etf1, Srgn, Txnrd1, Sqstm1, Nfkbia), suggesting they may be exposed to higher levels of noxious substances (Fig. 4G). Together, M_inflammatory cells display a pro-inflammatory profile characterized by a distinct transcriptomic signature.

We also examined the transcriptomal changes of other microglia subsets in Mr1−/− P301S mice. We focused on the three major microglia subsets (M_ribo_hi, M_ribo_Med, M_ribo_low). Notable similarity was observed in the transcriptomal changes in all these three subsets between Mr1−/− P301S and control Mr1+/+ P301S mice (Fig. 5, A-F). Specifically, the genes upregulated in each microglia subset in Mr1−/− P301S mice were found to be enriched in genes related with lipoprotein assembly and clearance, ribosomal proteins, and inflammatory responses to toxic substances (Fig. 5, A-F). Apoe, a lipoprotein gene highly expressed in human microglia of Alzheimer’s disease patients [31], was expressed much higher in all the three main microglia subsets in Mr1−/− P301S mice compared to those in Mr1+/+P301S mice (Fig. 5B, D, F). A few other lipoprotein assembly and clearance related genes, such as Lpl, Apoc1, Abcg1, Nceh1, Npc2, were also significantly upregulated in all three main microglia subsets in Mr1−/− P301S mice compared to Mr1+/+ P301S mice. A variety of ribosome biogenesis genes (e.g. Rps18, Rpl10a, Rps28, Rpl41, Rpl36a, Rpl39) were also expressed higher in all the three main microglia subsets in Mr1−/− P301S mice (Fig. 5, A-F). These genes encode ribosomal proteins, and their increased expression suggests enhanced ribosome biogenesis and gene translation. In addition, microglia in Mr1−/− P301S mice expressed higher levels of genes related to immune and inflammatory responses to toxic substances indicating that they might be exposed to higher levels of noxious substances (Fig. 5, A-F). Proinflammatory chemokines and cytokines, such as Ccl3, Ccl4, Il1b, and Tnf, were among the gene sets associated with responses to toxic substances. These proinflammatory chemokine and cytokine genes were upregulated in microglia of Mr1−/− P301S mice (Fig. 5B, D, F). Together, microglia in Mr1−/− P301S mice exhibit a proinflammatory profile.

Fig. 5
figure 5

Comparison of gene expression of the main microglia subset of hippocampus microglia between 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. A Enrichment of the indicated gene sets in M_ribo_hi cells from 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. B Violin plots show expression of representative genes that were differentially expressed in M_ribo_hi cells between 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. C Enrichment of the indicated gene sets in M_ribo_med cells from 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. D Violin plots show expression of representative genes that were differentially expressed in M_ribo_med cells between 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. E Enrichment of the indicated gene sets in M_ribo_low cells from 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. F Violin plots show expression of representative genes that were differentially expressed in in M_ribo_low cells between 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. Data are from 4 mice per group

Full size image

Our Mr1−/− mice were characterized and validated in previous studies. Of note, our snRNA-seq data detected Mr1 expression in cells from Mr1−/− P301S mice, but not in cells from Mr1+/+ mice (Fig. S7). These data verify the absence of MR1 expression in Mr1−/− mice.

We next performed QPCR to verify the gene expression in microglia that were FACS-sorted from the hippocampus of Mr1−/− P301S mice and control Mr1+/+P301S mice. Of note, Apoe was greatly upregulated in the hippocampal microglia of Mr1−/− P301S mice, compared to those in control Mr1+/+P301S mice (Fig. 6A). Expression of another lipoprotein Apoc1 was also increased in microglia from the hippocampus of Mr1−/− P301S mice. Microglia from Mr1−/− P301S mice also exhibited increased expression of the representative ribosome biogenesis gene Rps18, as well as genes that were upregulated in responses to toxic substances such as Spp1 and Rsad2. Transfer of MAIT cells reduced the expression of these genes in microglia from Mr1−/− P301S mice (Fig. 6B), verifying that the presence of MAIT cells repress the expression of these genes in hippocampus microglia of P301S mice. We then performed multiplex cytokine assays to verify whether the protein concentrations of proinflammatory cytokines in the brain homogenates of Mr1−/− P301S mice and control Mr1+/+P301S mice. The concentrations of proinflammatory cytokines including IL1b, IL1a, and TNF, were significantly increased in the brain homogenates of Mr1−/− P301S mice (Fig. 6C). Adoptive transfer of MAIT cells reduced the concentrations of these proinflammatory cytokines, indicating that the presence of MAIT cells repressed neuroinflammation in Mr1−/− P301S mice (Fig. 6D). Together, these data verify that MAIT cells repress microglial inflammation in P301S mice.

Fig. 6
figure 6

The presence of MAIT cells alters gene expression in microglia and represses proinflammatory cytokine concentrations in P301S mice. A mRNA levels of the indicated genes in microglia sorted from the hippocampus of 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. B mRNA levels of the indicated genes in microglia sorted from the hippocampus of 7-month-old Mr1−/− P301S mice with adoptive transfer of MAIT cells or PBS. C Concentrations of the indicated cytokines in the brain homogenate of 7-month-old Mr1−/− P301S mice and control Mr1+/+ P301S mice. D Concentrations of the indicated cytokines in the brain homogenate of 7-month-old Mr1−/− P301S mice with adoptive transfer of MAIT cells or PBS. Data are from 6 mice per group, representative of 2 independent experiments. Error bars = mean ± SEM. **p < 0.01. Sex information in Additional file 1

Full size image

Discussion

In this study, we revealed an important role of MAIT cells in regulating tau pathology and neurodegeneration in P301S transgenic mice and investigated the underlying mechanisms. Our findings demonstrated that MAIT cells are present in the meninges and express antioxidant molecules. We showed that the deficiency of MAIT cells leads to meningeal barrier leakage and examined microglial dysfunction in P301S mice lacking MAIT cells. Our data together suggest an important role for MAIT cells in repressing tau related neuroinflammation and neurodegeneration.

Increasing evidence indicates that lymphocytes particularly T cells may contribute to the regulation of brain homeostasis and neurodegeneration [5, 9,10,11,12]. MAIT cells are a unique type of innate-like T cells that are abundant in humans [32, 33]. Our previous work suggested that MAIT cells are present in the meninges of adult wildtype mice, where they express antioxidant molecules that help maintain meningeal barrier integrity [15]. We hypothesized that this barrier protective function is important to regulate tau pathology and neurodegeneration. In this study, we found that Mr1−/− P301S mice that lack MAIT cells exhibited meningeal leakage, microglial inflammation, and exacerbated tau pathology and neurodegeneration, compared to Mr1+/+ P301S mice. The MR1 molecule is a highly conserved molecule specialized in antigen presentation [17, 34,35,36,37]. Given its unique tertiary structure, we do not expect that the MR1 molecule has other significant functions not related to MAIT cells or other Mr1-restrictive T cells. In this study, we performed MAIT cell adoptive transfer experiments to verify the functional capability of MAIT cells in vivo. The transfer of MAIT cells restored meningeal barrier integrity and suppressed microglial inflammation and neurodegeneration in the Mr1−/− P301S mice. While we cannot yet establish a causal relationship among the phenotypic changes in Mr1+/+ P301S mice, our data collectively provide insights into a role of MAIT cells in regulating neuroinflammation and neurodegeneration in the context of tau pathology. Of note, the abundance of MAIT cells is highly variable and influenced by the microenvironment, particularly the microbiota [38,39,40]. Future research exploring the relationship between gut microbiota, MAIT cell development, and neurodegeneration could provide further insights into the mechanisms underlying neurodegenerative diseases.

Previous work indicates reactive microglia may lead to neurodegeneration in in vitro 3D human neuroimmune culture and exacerbate tau pathology in transgenic mouse models [5,6,7,8,9]. Conversely, increased tau pathology also induces microglia inflammation [4]. In our study, we observed a remarkable increase in proinflammatory cytokines in the hippocampus of Mr1−/− P301S mice, accompanied by a pronounced proinflammatory profile of microglia. Tau pathology is also notably increased in Mr1−/− P301S mice. While our results do not establish a causal relationship between elevated tau pathology and increased neuroinflammation in Mr1−/− P301S mice, we hypothesize that the elevated tau pathology and increased neuroinflammation might form a positive feedback loop, together exacerbating neurodegeneration. Future research to dissect the precise mechanistic pathways might be worthwhile.

Our scRNA_seq analysis identified a distinct microglia subset that accumulated in the hippocampus of Mr1−/− P301S mice, which we termed M_inflammatory. These cells exhibited proinflammatory phenotype. They mostly closely resemble the Microglia_chemokine mentioned in an earlier report [41]. However, because Microglia_chemokine cells were extremely rare in wildtype mice, detailed description of Microglia_chemokine was yet lacking in the earlier study, except that these cells express high levels of chemokines [41]. Here, we performed extensive transcriptomic analysis of M_inflammatory cells, and found that they express high levels of proinflammatory cytokines and genes related to immune and inflammatory responses to toxic substances. Our data indicate that M_inflammatory may represent a pro-inflammatory microglial subset that emerges in response to increased exposure to noxious substance. Further exploration of these cells in other pathological contexts and their specific roles in brain function and neurodegeneration might be an important avenue for future research.

Our study has several limitations. The microglia analyses in this study were performed at a relatively early age in which tau pathology was yet moderate. While our results focused on the early changes in microglia, future research exploring longer time points might provide insights into the role of MAIT cells in regulating neuroinflammation along the disease progression. Additionally, our flow cytometry analyses did not reveal significant infiltration of MAIT cells into the brain parenchyma of P301S mice. The experimental procedures involved in flow cytometry analyses, such as enzymatic digestion and Percoll centrifugation, may inevitably cause cell loss or damages to TCR structures. Therefore, we cannot exclude the possibility that a small number of MAIT cells might be present in the brain parenchyma of adult P301S or wildtype mice. Moreover, the abundance of MAIT cells is highly dependent on microbiota, and thus it is expected that MAIT cell abundance may vary across mice bred in different animal facilities at different institutions. Additionally, the abundance of MAIT cells may change in certain pathological conditions. Previous work indicates MAIT cell infiltration into the brain parenchyma of 5xFAD mice, where they interact with microglia to influence Amyloid b pathology [42]. Future studies to understand the ontogeny and functional similarities and divergence between meningeal MAIT cells and those infiltrating the brain parenchyma might be worthwhile.

Conclusion

In conclusion, we report that MAIT cells were present in the meninges of P301S mutant human tau transgenic mice and retain expression of antioxidant molecules. The absence of MAIT cells exacerbates tau pathology and neurodegeneration in P301S mice. MAIT cells protect meningeal integrity and repress neuroinflammation in P301S mice. Together, these results indicate that a role of MAIT cells in regulating neurodegenerative tau pathology.

Availability of data and materials

snRNA-seq data were deposited at Gene Expression Omnibus (accession number GSE285822).

Abbreviations

MAIT:

Mucosal-associated invariant T cells

MR1:

MHCI-related

APC:

Antigen presenting cells

FACS:

Fluorescence activated cell sorting

snRNA-seq:

Single nucleus RNA sequencing

UMAP:

Uniform manifold approximation and projection

GSEA:

Gene set enrichment analysis

cDNA:

Complementary DNA (cDNA)

M_inflammatory:

Inflammatory microglia

ISG:

Interferon stimulated gene

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Acknowledgements

We thank Drs. Zhiping Pang and Arnold Rabson for helpful discussion.

Funding

This work was supported by the U.S. National Institutes of Health Grants R01HL155021 (QY), RF1AG078459 (QY), and support to the Child Health Institute of New Jersey from the Robert Wood Johnson Foundation (Grant #74260).

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  1. Yuanyue Zhang, Zhi Yang, Na Jiang have contributed equally to this work.

Authors and Affiliations

  1. Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, 89 French St, New Brunswick, NJ, 08901, USA

    Yuanyue Zhang, Zhi Yang, Na Jiang, Xiaosheng Tan & Qi Yang

  2. Rutgers Institute for Translational Medicine and Science, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA

    Gaoyuan Cao & Qi Yang

  3. Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, 08854, USA

    Peng Jiang

  4. Department of Pediatrics, Johnson Medical School, Rutgers Robert Wood, New Brunswick, NJ, 08901, USA

    Qi Yang

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Contributions

Y.Z., Z.Y., J.N.,X.T., P.J., G.C., and Q. Y. performed the experiments and analyzed the data. Z.Y. performed bioinformatics analysis. Y.Z., Z.Y., J.N., and Q.Y. wrote the manuscript. All authors approved the manuscript.

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Correspondence to Qi Yang.

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Zhang, Y., Yang, Z., Jiang, N. et al. MAIT cell deficiency exacerbates neuroinflammation in P301S human tau transgenic mice. J Neuroinflammation 22, 90 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12974-025-03413-7

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