Researchers traced an immune pathway from brain-draining lymph nodes to tau-affected tissue, revealing how peripheral immune activity may become intertwined with neurodegeneration.
Study: Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration. Image Credit: Antonio Marca / Shutterstock
In a recent study published in the journal Nature Neuroscience, researchers in the United States assessed the role of conventional type 1 dendritic cells (cDC1s) in tau-mediated neurodegeneration.
Tauopathies are neurodegenerative disorders characterized by intracellular accumulation of hyperphosphorylated tau protein. These include Alzheimer’s disease (AD) and some types of frontotemporal dementia. Tauopathy is accompanied by an increase in T lymphocytes in the brain, especially cluster of differentiation 8 (CD8+) cytotoxic T cells.
The authors previously reported that T cell depletion attenuated tau-mediated neurodegeneration in P301S tau transgenic mice expressing human apolipoprotein E4 (TE4 mice), suggesting a role for T cells in neurodegeneration. cDC1s, which are specialized antigen-presenting cells, cross-present antigens to prime CD8+ T cells to become effector cells across various disease conditions. However, whether cDC1s cross-prime brain-specific CD8+ T cells in tau-mediated neurodegeneration remains unknown.
The study and findings
In the present study, researchers evaluated the role of cDC1s in tau-mediated neurodegeneration. First, they generated four cohorts of mice, TE4Δ+32 (tau-expressing, cDC1-deficient), TE4WT (tau-expressing, cDC1-sufficient), E4Δ+32 (non-tau, cDC1-deficient), and E4WT (non-tau, cDC1-sufficient), and investigated the impact of cDC1 deficiency on neuropathology.
Both female and male TE4WT mice exhibited marked regional brain atrophy, with tissue loss in the piriform cortex, entorhinal cortex (PEC), and hippocampus, and enlargement of the lateral ventricles compared to E4WT mice. Conversely, PEC and hippocampus were preserved in TE4Δ+32 mice, with a trend toward a decrease in lateral ventricle volume, compared to TE4WT mice.
Only male TE4Δ+32 mice had significantly lower plasma levels of neurofilament light chain (a neurodegeneration biomarker) than TE4WT mice. Moreover, cDC1 levels were extremely low in TE4WT brains, even with evident brain atrophy. cDC1 deficiency did not markedly affect tau phosphorylation or aggregation, although small changes were detected in some soluble tau measures, but it reduced astrocyte and microglial reactivity, particularly in male mice.
cDC1 deficiency also preserved excitatory neuronal populations, while microglial activation was partially modulated with no major population shifts. The proportion of CD8+ T cells was also markedly lower in E4Δ+32 and TE4Δ+32 mice than in E4WT and TE4WT mice, respectively. Meanwhile, cDC1-deficient mice showed corresponding higher proportions of other lymphocytes, including natural killer T cells, natural killer cells, and CD4−CD8− T cells.
Flow cytometry analyses revealed a five-fold higher brain infiltration of CD45hi leucocytes in TE4WT mice (relative to E4WT) but a 40% reduced frequency of these cells in TE4Δ+32 mice. cDC1-deficient mice also had about 50% fewer brain-infiltrating T cells. Although CD4+ T cells increased with tau pathology, their frequency among total brain cells was similar between TE4Δ+32 and TE4WT mice.
By contrast, CD8+ T cell frequency was substantially lower in TE4Δ+32 mice than in TE4WT mice, suggesting cDC1s are required for efficient CD8+ T cell recruitment to the brain during tau-mediated neurodegeneration. cDC1 deficiency also reduced the activation and clonal expansion of CD8+ T cells in the brain. The team also observed, using model antigens delivered to the brain, that cDC1-mediated cross-presentation predominantly occurred in deep cervical lymph nodes (dCLNs).
This cDC1-mediated cross-presentation was critical for CD8+ T cell responses in the brain, and genetic disruption of Wdfy4, which is required for cDC1 cross-presentation, was similarly protective against tau-mediated neurodegeneration. Next, the team assessed the neurotoxic potential of TE4 T cells. T cells derived from the brain tissues and dCLNs of TE4 mice with neurodegeneration (and from E4 controls) were intracranially injected into the hippocampus of TE4 mice with mild tau pathology and no overt atrophy.
After eight weeks, T cells accumulated in contralateral and ipsilateral brain regions. The overall T cell counts were similar between recipients of E4 and TE4 T cells. However, recipients of TE4 T cells showed elevated glial activation in both hemispheres, suggesting that TE4 T cells can induce glial activation and neuroinflammatory responses in the absence of detectable neuronal loss at that time point.
Next, the researchers analyzed published aging datasets to examine whether cDC1s exhibit age-dependent changes. The frequencies of four subsets of dendritic cells (DCs) in peripheral blood were stable across five human age groups. Transcriptional analyses of major antigen-presenting genes indicated minimal changes associated with aging.
The team also analyzed a single-cell RNA-sequencing dataset of cerebrospinal fluid (CSF) immunocytes from healthy people and individuals with AD or mild cognitive impairment (MCI). There were no significant differences in the abundance of dendritic cell subsets or in their antigen-presentation-related transcriptional profiles between healthy subjects and individuals with AD or MCI, indicating that these measured CSF DC features were broadly similar across groups. A separate analysis of meningeal dendritic cells similarly found no significant differences in cDC1 or cDC2 abundance or antigen-presentation-related gene expression between healthy controls and individuals with AD.
The researchers then examined whether T-cell infiltration extended to other tauopathies and humans. A mouse model of frontotemporal dementia showed increased brain T cells, while postmortem tissue from people with primary tauopathies, including progressive supranuclear palsy, Pick’s disease, and corticobasal degeneration, showed markedly increased parenchymal CD8+ T-cell infiltration in gray and white matter compared with controls. However, the direct involvement of cDC1s in these human samples was not established.
Conclusions
Collectively, the findings indicate that, in this mouse model of tauopathy, antigen cross-presentation by cDC1s is crucial for the initial priming of CD8+ T cells in brain-draining dCLNs, allowing brain infiltration and contributing to neurodegeneration.
The authors posit that tauopathy-induced neuronal injury leads to the release of antigens, which are captured by cDC1s to prime CD8+ T cells. Notably, the antigenic drivers of cDC1-based T-cell infiltration remain unknown, although immunopeptidomic analysis identified candidate MHC-bound peptides derived from proteins including tau, stathmin-3, and neurofilament light chain.
Further research is needed to determine which antigens drive the T-cell response and whether the same cDC1-dependent mechanism operates in human tauopathies.
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