Peripheral dendritic cells prime CD8+ T cells in lymph nodes to drive tau-mediated neurodegeneration
核心洞察
Researchers traced an immune pathway from brain-draining lymph nodes to tau (搜索)-affected tissue, showing peripheral immune activity intertwines with neurodegeneration.
Conventional type 1 dendritic cells (cDC1s) (搜索) cross-present brain antigens in deep cervical lymph nodes, priming CD8+ T cells (搜索) that infiltrate the brain and worsen tau (搜索)-mediated damage.
Eliminating cDC1s or disrupting cross-presentation (via Wdfy4) reduced brain T-cell infiltration, preserved brain regions, and protected cognition in tauopathy (搜索) mouse models without altering tau (搜索) tangles.
Immune cells that normally protect the body by attacking foreign or infected cells are found at much higher levels in the brains of patients with Alzheimer's disease (搜索) and related disorders than in healthy brains. These cells appear to contribute to neurodegeneration, but where they came from and how they were primed to accumulate in the brain had been unknown. Researchers at Washington University School of Medicine in St. Louis (搜索) have now discovered in mice that these immune cells, known as T cells, receive their instructions from lymph nodes outside the brain, and that blocking these instructions can dramatically mitigate neurodegeneration.
The study, published Sept. 3 in Nature Neuroscience, reveals a previously unsuspected pathway that could potentially halt or slow the progression of Alzheimer's disease (搜索) and other diseases collectively called primary tauopathies, which are characterized by twisted clumps of tau (搜索) protein that accumulate in the brain.
A driver of neurodegeneration originating outside the brain
Tauopathies are neurodegenerative disorders characterized by intracellular accumulation of hyperphosphorylated tau (搜索) protein, including Alzheimer's disease (搜索) (AD) and some types of frontotemporal dementia (搜索). Tauopathy (搜索) 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 (搜索)-mediated neurodegeneration in P301S tau transgenic mice expressing human apolipoprotein E4 (TE4 mice), suggesting a role for T cells in neurodegeneration. Conventional type 1 dendritic cells (cDC1s) (搜索), specialized antigen-presenting cells, cross-present antigens to prime CD8+ T cells (搜索) to become effector cells across various disease conditions. However, whether cDC1s cross-prime brain-specific CD8+ T cells in tau-mediated neurodegenereration remained unknown.
David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor in WashU Medicine's Department of Neurology and the study's senior author, emphasized the therapeutic significance of a driver that originates outside the brain. "One of the issues in developing treatments for neurological diseases is that you need to engineer your treatment so that it gets into the brain and past the blood-brain barrier, but we might not actually need to get the drugs into the central nervous system to mitigate neurodegeneration," Holtzman said. "There are lots of ways to manipulate T cells that have been studied extensively and that are approved treatments for other diseases, but many haven't yet been explored for neurodegenerative diseases."
cDC1s are required for CD8+ T cell recruitment to the brain
To evaluate the role of cDC1s, the researchers generated four cohorts of mice: TE4Δ+32 (tau (搜索)-expressing, cDC1-deficient), TE4WT (tau-expressing, cDC1-sufficient), E4Δ+32 (non-tau, cDC1-deficient), and E4WT (non-tau, cDC1-sufficient). 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, the 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. Notably, cDC1 levels were extremely low in TE4WT brains even with evident brain atrophy, and cDC1 deficiency did not markedly affect tau (搜索) phosphorylation or aggregation, although small changes were detected in some soluble tau measures. However, cDC1 deficiency reduced astrocyte and microglial reactivity, particularly in male mice, and preserved excitatory neuronal populations.
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. While CD4+ T cells increased with tau (搜索) 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 (搜索) in the brain.
Cross-presentation occurs in deep cervical lymph nodes
Using model antigens delivered to the brain, the team observed 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 (搜索)-mediated neurodegeneration.
Holtzman explained that while the specific trigger causing dendritic cells to activate the T cells is not known, it is likely that tau (搜索)-induced damage to brain cells releases material that finds its way from the brain into the lymph nodes in the neck. There, dendritic cells flag that material as a target for T cells to attack.
To assess the neurotoxic potential of TE4 T cells, the researchers intracranially injected T cells derived from the brain tissues and dCLNs of TE4 mice with neurodegeneration (and from E4 controls) into the hippocampus of TE4 mice with mild tau (搜索) 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.
Cognitive protection without altering tau tangles
Eliminating dendritic cells from the lymph nodes as well as other locations in mice that ordinarily develop tau (搜索) tangles and neurodegeneration also wiped out the elevated levels of T cells, particularly CD8 T cells, in the brain and the attendant brain damage. This was true even though there was no change in the levels of tau tangles in the brain. In addition to these cellular changes, the mice also retained their cognitive abilities, which suggests that halting the activity of the T cells may slow or reduce the cognitive decline characteristic of Alzheimer's disease (搜索).
Relevance to human tauopathies
The researchers examined whether T-cell infiltration extended to other tauopathies and humans. A mouse model of frontotemporal dementia (搜索) showed increased brain T cells, while postmortem tissue from people with primary tauopathies, including progressive supranuclear palsy (搜索), Pick's disease (搜索), and corticobasal degeneration (搜索), 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.
Analyses of published aging datasets indicated that the frequencies of four subsets of dendritic cells in peripheral blood were stable across five human age groups, with minimal transcriptional changes in major antigen-presenting genes associated with aging. A single-cell RNA-sequencing dataset of cerebrospinal fluid (CSF) immunocytes from healthy people and individuals with AD or mild cognitive impairment (MCI) showed no significant differences in dendritic cell subset abundance or antigen-presentation-related transcriptional profiles between 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.
Toward a non-brain therapeutic strategy
The identification of this non-brain immune pathway offers several potential therapeutic targets. Holtzman's team is investigating whether impeding dendritic cell function in midlife, to match the onset of tau (搜索) protein tangles, is as effective as blocking it at birth, as in this study. His team is also pursuing ways to identify what specific signal the T cells are using to home in on the brain, in order to block it.
"Until not that long ago, most people, including myself, did not think that the immune response was even involved in neurodegenerative diseases that are due to protein accumulation in the brain," Holtzman said. "That these dendritic cells are involved in neurodegenerative disease is exciting; we've shown they're important, and that they are a potential target for future therapy."
The antigenic drivers of cDC1-based T-cell infiltration remain unknown, although immunopeptidomic analysis identified candidate MHC-bound peptides derived from proteins including tau (搜索), 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.