Abstract
Neurodegenerative diseases activate innate and adaptive immune responses that can either slow or accelerate disease progression. Here, we sought to define beneficial immune pressures that emerge during tauopathy development in mice and humans. Using mice that express mutant human tau in neurons, we observed that microglia slowed tauopathy development by controlling the spread of phosphorylated tau (pTau) in the central nervous system and blood. However, over time microglia converted into distressed antigen-presenting cells, acquired neuronal transcripts and were targeted by resident, clonally expanded CD8+ T cells. These cells did not express traditional effector molecules, such as IFNγ, TNF or granzymes a/b/c, but instead deposited granzyme K (GZMK) onto microglia and were regulated by immune checkpoint proteins (TIGIT, PD-1), as blockade of TIGIT and PD-1 enhanced disease progression. GZMK+CD8+ T cells also targeted microglia in pTau-rich human brain lesions resulting from age, Alzheimer’s disease or chronic traumatic encephalopathy. Deletion of CD8+ T cells in mice promoted the emergence of distressed microglia containing neuronal transcripts, markedly enhanced pTau spread and accelerated neurological decline. These data demonstrate that GZMK+CD8+ T cells are a signature of tauopathy development and could potentially be harnessed to slow disease progression.
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Data availability
There are no restrictions on data availability. The bulk and single-cell RNA-seq data are available in the NCBI Gene Expression Omnibus (GEO) under accession codes GSE273752 (Figs. 5 and 6 and Extended Data Fig. 5), GSE273753 (Fig. 7 and Extended Data Figs. 8 and 9) and GSE273757 (Fig. 2 and Extended Data Fig. 3). Source data are provided with this paper.
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Acknowledgements
This work was supported by the intramural program at the National Institute of Neurological Disorders & Stroke (NINDS) and the National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), as well as The Defense Health Agency (grant nos. 312516-5.00-67721 and 314223-5.00-67470). We thank A. Elkahloun and B. Sisay in the National Human Genome Research Institute Microarray Core for their assistance with the bulk and single-cell RNA-seq experiments. This study utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). The opinions and assertions expressed herein are those of the authors and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences or the Department of Defense.
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D.B.M. and H.D.M. wrote the manuscript. D.B.M., H.D.M., Y.L.L., C.T.B. and M.M.-S. designed experiments and interpreted results with input from co-authors. C.T.B. with support from M.M.-S. performed and analyzed all AIMS experiments. D.P.P. provided human brain tissue. D.M. performed multiplex immunohistochemistry and in situ hybridization experiments. K.R.J. performed bioinformatic analyses on single-cell RNA-seq data. H.D.M., V.A.G. and C.L. with support from J.M.G. performed and analyzed Simoa experiments. H.D.M., Y.L.L., C.T.B., C.E.D., P.C.D., A.M.J. and M.M. performed mouse experiments and collected data.
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Extended data
Extended Data Fig. 1 Characterization of immune cells in the spinal cords of P301S+/+ mice.
a, Bar graphs show the normalized number of homeostatic microglia, CD19+ B cells, Ly6G+ neutrophils, and Ly6C+ monocytes from the P301S−/−, P301S+/−, and P301S+/+ mice described in Fig. 1a, b. Data represent two independent experiments. ns ≥ 0.05, using a one-way ANOVA with Fisher’s LSD test. b, A concatenated contour plot shows the frequency of CD103+ CD8+ T cells in the spinal cords P301S+/+ mice (n = 7) at 31 to 33.5 weeks of age. The plot was pre-gated on the following markers: CD45+ TCRβ+ CD4− CD8+ . Percentages are provided in each quadrant. c, Graph shows the normalized number of CD103+ CD8+ T cells in the spinal cords of P301S−/− (n = 6), P301S + /-(n = 7), and P301S+/+ (n = 7) mice. Data represent two independent experiments. ns ≥ 0.05, *P = 0.0278, **P = 0.0043 using a one-way ANOVA with Fisher’s LSD test. All graphs in this figure show mean ± s.d., and the dots represent individual animals.
Extended Data Fig. 2 pTau staining in P301S −/− mice and gating strategy to identify microglia subpopulations.
a, Representative image shows pTau (AT8) staining (green) in the spinal cord of a P301S−/− control mouse (n = 6). Nuclei are blue. Location of magnified inset image is denoted by a white box. b, Representative FACS plots of leukocytes from the spinal cord of a P301S+/+ mouse show the gating strategy used to identify microglia in Fig. 1e,f. c, Histograms depict expression of CD45, CX3CR1, P2RY12, CD11b, F480, CD11c, and MHCII as well as FSC and SSC on homeostatic microglia (blue), CD11c+ microglia (green), CD11c+ MHCII+ microglia (pink) described in Figs. 1e,f and 7d,e.
Extended Data Fig. 3 Differentially regulated genes and pathways in the spinal cords of P301S+/+ mice.
This network interactome generated automatically using Ingenuity Pathway Analysis shows genes and pathways that were found to be differentially regulated in the spinal cords of P301S+/+ mice at 28 weeks of age using bulk RNA-seq. See Fig. 2a–d for additional analyses and information about the mouse groups.
Extended Data Fig. 4 Identification of TCR clusters using AIMS analysis.
a, UMAP projection of biophysical properties of identified TCR sequences are colored by either cluster membership (left) or sample identifier (right). Unclustered sequences are represented by white dots in the left panel. b, AIMS encoding of isolated TCR sequences from clusters 63 and 65 (as circled in a). Each color in the encoding represents an amino acid, while the white space represents padded zeros between each CDR loop. c, Quantification of cluster purity using the Shannon entropy, a metric to measure diversity. The full dataset is nearly maximally diverse (4.2 bits is the maximum entropy for proteins), whereas both clusters show a much lower diversity due to the high similarity of the sequences in each cluster. d-e, Gene expression profiles for the TCR sequences in cluster 63 (d) or cluster 65 (e). Cells correspond 1:1 with those in panel b. f, Relative expression of a few key genes across the collected biological samples. Violin plots give the distributions of the normalized expression, whereas the lines give the quartiles of each distribution.
Extended Data Fig. 5 Analysis of CD8+ and CD4+ TCR clusters during tauopathy.
a, Sequence logos are provided for five additional CD8+ T cell clusters (1, 2, 3, 5, 6) shown Fig. 5 as well as the consensus sequence alignment. b, Claudrogram plot depicts 9 different expanded CD4+ T cell clusters found primarily in the spinal mediastinal lymph nodes of P301S+/+ mice. Each numbered cluster in the tree is a distinct color. Dot size corresponds to the sequence expansion count, and dot color denotes sample type. LN, lymph node (purple); SC, spinal cord (red).
Extended Data Fig. 6 GzmK+ CD8+ T cells target pTau+ brain lesions in humans.
pTau+ brain lesions are shown for patients with chronic traumatic encephalopathy (CTE) (a, b), Alzheimer’s disease (AD) (c, d) and age-related tauopathy (e, f). Representative immunofluorescence images from patient brain sections in a, c, and e show immunofluorescence staining for pTau (magenta), NeuN (blue), nuclei (white), and GzmK+ CD8+ T cells (yellow dots). The pTau+ lesion in each image is outlined with a dotted white line. Magnified images in b, d, and f show immunohistochemical staining for pTau (brown) in adjacent brain sections from each patient. Nuclei (purple) are labeled with hematoxylin. Dotted black lines demarcate the corresponding areas from a, c, and e.
Extended Data Fig. 7 Quantification of spinal cord GZMK and serum GFAP and NF-L in P301S+/+ CD8KO mice.
a, Representative spinal cord images show the distribution of CD8+ T cells (yellow spots), pTau (red), and GZMK (cyan) in the spinal cords of P301S+/+ CD8WT (n = 5) and P301S+/+ CD8KO (n = 4) mice at 30 weeks. b, Bar graph shows quantification of CD8+ T cell numbers divided by spinal cord tissue area (µm2) for the images in a. *P = 0.0113, **P = 0.0025 using one-way ANOVA with Tukey’s test. c, Bar graph show quantification of GZMK area divided by spinal cord tissue area (µm2). Data were normalized using a log transformation: log10(x + 1). *P < 0.05 using one-way ANOVA with Newman-Keuls test. d, Quantification of GFAP and NF-L proteins (pg/mL) in the blood of the mouse groups described in Fig. 7c. ns ≥ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001 using one-way ANOVA with Fisher’s LSD test. All dots in b-d represent individual animals, and graphs show mean ± s.d.
Extended Data Fig. 8 A microglia subcluster from P301S+/+ CD8KO mice contains neuronal transcripts.
a, Heatmap shows expression of microglia (gray) or neuronal (black) signature genes in neuronal partition 8 as well as microglia partitions 2 and 11 shown in b. b, UMAP depicting drill-down analysis of microglia partitions 2 and 11 combined with neuronal partition 8 from Fig. 8a. Each color indicates a different partition or cluster. The black arrow denotes the partition 2 cluster 1 CD8KO only microglia subcluster. c, Heatmap of top pathways upregulated in a population of microglia population found only in the spinal cords of P301S+/+ CD8KO mice (partition 2 cluster 1 CD8KO only) relative to other microglia clusters. See Fig. 8c for mouse groups and information about the different microglia clusters identified by sc-RNAseq.
Extended Data Fig. 9 Microglia from P301S+/+ mice show an enhanced cell death gene expression signature.
a, Absolute number of microglia in each subcluster from Fig. 8c for the denoted groups. b, Dot plot demonstrates the top functions and corresponding Z scores that were either increased or decreased in microglia partition 2 from the spinal cords of 30-week-old P301S+/+ CD8WT mice relative to age-matched P301S+/+ CD8KO controls. Dot size denotes the number of overlapping genes and color indicates the level of significance. See Fig. 8c information about the different microglia partitions and clusters identified by sc-RNAseq.
Extended Data Fig. 10 Analysis of microglia neural transcripts and Y-maze performance.
a, Representative images from the spinal cord of a P301S−/− CD8WT mouse (n = 3) show Iba1+ myeloid cells (green), NeuN neurons (blue; white asterisks), nuclei (white), and four neural transcripts - Tuba1a (yellow), Map1b (teal), Pcsk1n (pink), and Nefl (orange). The white dotted line outlines an individual Iba1+ myeloid cell. b-c, Two representative images from the spinal cord white matter of P301S+/+ CD8KO mice (n = 5) show Iba1, NeuN, nuclei, Tuba1a, Map1b, Pcsk1n, and Nefl. Multinucleated Iba1+ myeloid cells are outlined with white dotted lines. White arrows denote nuclei within a multinucleated Iba1+ cell that are densely positive for neural transcripts. d, Bar graph shows the slope of the linear regression line for Y-maze performance (triplicate ratios) over a 3-week period for the mouse groups described in Fig. 8f. ns ≥ 0.05, using one-way ANOVA with a Newman Keuls test. e, Bar graph shows the slope of the linear regression line for Y-maze performance (arm entries) over a 3-week period in P301S+/+ mice treated with isotype (n = 7) or anti-PD1/TIGIT (n = 12) antibodies beginning at 21 weeks. P value was calculated using two-tailed Student’s t test. Data are representative of two independent experiments. All dots in d,e represent individual animals, and graphs show mean ± s.d.
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Supplementary Table 2. CD8+ T cell gene expression module.
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Supplementary Table 3. Expanded T cell clones.
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Mason, H.D., Latour, Y.L., Boughter, C.T. et al. Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia. Nat Immunol 26, 1152–1167 (2025). https://doi.org/10.1038/s41590-025-02198-4
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DOI: https://doi.org/10.1038/s41590-025-02198-4
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