Microglia and GZMK+ CD8+ T Cells: A Protective Axis Against Tau Pathology in Neurodegenerative Diseases

         Neurodegenerative diseases are characterized by the core pathology of abnormal phosphorylated Tau (pTau) deposition and transregional spread. Traditionally, research has focused on neuronal events, but growing evidence suggests that central immune cells, particularly microglia and T cells, play significant roles in regulating tau pathology progression. However, whether these immune cells act as "promoters" or "protectors" has long been debated. A study published in Nature Immunology by the National Institutes of Health, using P301S Tau mice as a model, employed high-dimensional flow cytometry, transcriptomics, TCR sequencing, and multiplex immunohistochemistry to uncover the interaction between CD8+ T cells and microglia.

Microglia Activation Correlates with pTau Deposition

         Researchers conducted high-parameter flow cytometry on the spinal cord and brain regions of P301S mice, detecting the recruitment of various immune cells, with a significant increase in CD11c+MHCII+ microglia exhibiting characteristics similar to disease-associated microglia (DAM). These activated subsets were closely associated with high levels of pTau deposition in spinal cord gray matter, suggesting they contribute to the inflammatory response and may play a critical role in either controlling or amplifying tau spread. This forms the backdrop of a tauopathy-specific "disease-associated immune ecosystem."

Figure 1. Tau promotes immune cell recruitment and activation

Transcriptomics Reveals Inflammation and Antigen Presentation

         In 28-week-old mice, transcriptomic analysis revealed active IL-6, complement, and Fc receptor inflammatory pathways, indicating a highly active neuroinflammatory landscape, while cholesterol synthesis and metabolism pathways were downregulated. Microglia displayed antigen presentation and inflammatory activation features. These transcriptional patterns aligned with flow cytometry results, confirming microglia as key drivers of inflammation during disease progression. Depleting microglia with a CSF-1R inhibitor led to a significant increase in cortical pTau and higher mortality, demonstrating that microglia play a role in suppressing pathological spread at this stage.

Figure 2. CSF-1R inhibition leads to increased tau deposition and neurodegenerative decline

CD8+ T Cells Directly Interact with Microglia

         Immunohistochemistry revealed substantial CD8+ T cell infiltration in the spinal cord, with approximately 76% directly contacting Iba1+ microglia, suggesting a specific immune interaction. This phenomenon was not limited to mouse models but was also observed in human brain tissue from Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and age-related lesions. These findings indicate that CD8+ T cells are selectively recruited to tau-related pathological regions and regulate disease progression through interactions with microglia.

Figure 3. CD8+ T cells interact with microglia in mouse and human tauopathies

GZMK+ CD8+ T Cells as Key Effector Subset

         Single-cell sequencing and TCR analysis showed that infiltrating CD8+ T cells exhibited clonal expansion and were marked by high Granzyme K (GZMK) expression, without expressing traditional effector molecules like IFNγ or GZMB. In both mouse spinal cords and human pTau lesions, GZMK+ CD8+ T cells were abundant and deposited GZMK protein on microglia surfaces. These deposits suggest they may regulate or clear damaged microglia to maintain tissue homeostasis, rather than directly inducing neuronal death. This non-conventional effector mode offers new insights into the role of CD8+ T cells in neurodegenerative diseases.

Figure 4. GZMK+ CD8+ T cells target microglia in mouse and human tauopathies

CD8 Depletion Accelerates pTau Spread and Neurodegeneration

         To validate these findings, researchers created a CD8-deficient model in P301S mice. At 31 weeks, these mice showed higher brain and blood pTau levels, along with elevated neuronal damage markers like GFAP and neurofilament light chain. Microglia were hyperactivated, resembling a late-stage pathological ecosystem. Notably, in CD8-deficient mice, microglia exhibited an abnormal state carrying neuronal transcripts, suggesting phagocytosis or uptake of adjacent neuronal components. This pathological change was closely linked to accelerated functional decline. Further experiments showed that blocking immune checkpoint molecules PD-1/TIGIT weakened CD8+ T cell regulation, also accelerating disease progression. Thus, GZMK+ CD8+ T cells not only limit pTau spread by clearing damaged microglia but also require immune checkpoints to maintain functional balance.

Figure 5. CD8+ T cells reduce microglia containing neuronal transcripts, regulated by PD-1/TIGIT

         Tau, a microtubule-associated protein, maintains neuronal cytoskeleton stability. In AD and other tauopathies, abnormally phosphorylated tau forms neurofibrillary tangles, leading to neuronal damage and signaling deficits. Tau pathology exhibits "trans-neuronal spread," causing cascading deterioration. This study's discovery of the microglia–GZMK+ CD8+ T cell axis offers a new perspective on suppressing tau spread. Combined with prior findings on microglia pathways like TREM2, this study highlights the protective role of specific T cell subsets, providing new potential targets for immunotherapy.

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