CD8+ T cells are primed by cDC1 and exacerbate tau-mediated neurodegeneration

Keywords

● Neurodegeneration

● Tauopathy

● Dendritic cells

● CD8+ T cells

Main Findings: CD8+ T cells drive neuropathology in aging and neurodegenerative disease by promoting inflammatory glial cell activation and neuronal loss. These cells are also clonally expanded in mouse and human neurodegeneration. However, the mechanisms by which CD8+ T cells become primed to cause damage in an antigen-dependent manner are not understood. In this preprint, Hu et al. investigate whether type 1 conventional dendritic cells (cDC1s) prime CD8+ T cell-mediated neurodegeneration in a model of tauopathy. The authors use a mouse model where cDC1s are selectively absent from development to ask how their deficiency, and the loss of the ability to cross-present antigen to prime CD8+ T cells, alters neuropathology in the chronic neurodegenerative stage of tauopathy. They explore this question in a mouse model where an enhancer upstream of Irf8 is knocked out (first developed in Durai et al. Nature Immunology 2019; PMID: 31406378), leveraging the fact that this enhancer specifically regulates Irf8expression in cDC1s but not cDC2s, peripheral macrophages, microglia, or T cells. They observe that loss of cDC1s prevents inflammatory microgliosis, while reducing reactive astrocytes, brain atrophy, and ventricular enlargement in tauopathy. This neuroprotection occurs despite no overt changes in aggregated tau, indicating that regulation of disease pathology is primarily immune mediated rather than related to proteotoxicity.

They then define how cDC1 deficiency alters the T cell repertoire in tauopathy using paired brain single cell RNA sequencing and TCR sequencing. They observe that the bulk of CD8+ cells in tauopathy are comprised of a PD-1+ TOX+ exhausted-like subset undergoing persistent antigen stimulation, with the dominant TCR clones in disease occupying this subset. However, the absence of cDC1s prevents the expansion of these cells, with dominant CD8+ TCR clones instead adopting a naïve phenotype. Instead, cDC1 deletion increases innate-like lymphocytes such as NK cells, while promoting the clonal expansion of NKT and CD4+ T cells. Dominant TCR clones are also enriched within proliferating lymphocytes, suggesting that clonal expansion is driven by responses to local brain antigens. Given this requirement for cDC1s in driving T cell-mediated neurodegeneration, they then define how these cells prime lymphocytes against brain-derived antigens. Transplantation of neurons expressing membrane-tethered ovalbumin into mice primes peripheral OT-1 ovalbumin-specific CD8+ T cells in a cDC1-dependent manner. Priming against brain-derived antigens is also tissue-specific: while antigen-specific CD8+ T cells expand in the brain-draining deep-cervical lymph node, and to a lesser extent the spleen, these responses are absent in the brain and meningeal tissue that borders it. Together, these findings identify that cDC1s prime antigen-specific CD8+ T cells to cause neurodegeneration in a mouse model of tauopathy.

Limitations: This study profiles the mechanisms by which CD8+ T cells are primed in neurodegenerative disease, an understanding of which is lacking. Limitations of this study include:

● First, the authors do not resolve the nature of the specific antigens that CD8+ cells respond to in tauopathy. While TCR clonality and activation data show evidence of antigen-experienced remodelling, the antigenic specificity of these clones remains unresolved, limiting interpretation of whether this represents tau-specific, broader brain self-antigen-directed, or non-brain-specific antigenic responses. An understanding of whether these CD8+ T cell responses are also limited to broad brain-derived antigens would also better identify whether priming is occurring specifically due to escape of antigen into the proximal lymph nodes.

● Second, the use of a constitutive cDC1 deficiency model limits temporal clarity in the role that cDC1s play in regulating CD8+ T cell priming. Inducible or stage-specific depletion would help further understand whether cDC1s are disease-initiating or disease-amplifying, as well as whether they are continuously required for pathology. This is especially important given that tau pathology can accumulate early in this model, whereas CD8+ T cells only infiltrate the brain with age. Further profiling of the temporal aspect of this by analysis of lymph node cDC1-CD8+ T cell responses at multiple disease stages would also inform as to whether age modulates T cell priming or recruitment to alter disease course.

● Third, while the regional aspect of the CD8+ T cell response to brain-derived antigens is explored in health, an exploration of this axis in tauopathy is lacking. While ovalbumin does not increase meningeal OT-1 T cell expansion in healthy mice, this may not translate to a disease setting. Indeed, Hobson et al. Nature Immunology2026 has shown that clonally expanded CD8+ T cells in Alzheimer’s disease increase in the leptomeninges (PMID: 41593242), and other studies have provided evidence for clonal expansion within the brain-enveloping cerebrospinal fluid (e.g., Gate et al. Nature 2020 PMID: 31915375). This suggests that while these responses are absent at steady-state, antigen encounter and antigen-specific retention and reactivation may increase within brain-associated tissues in chronic disease.

● Finally, the study focuses primarily on the cDC1-CD8+ T cell axis, but some transcriptomic data suggests that cDC1 deficiency may also reshape CD4+ T cell states, with observed increases in a cluster of regulatory T cells and increased CD4+ T cell clonal expansion. While flow cytometry for FOXP3+ CD44+ regulatory T cells suggests that this is limited to their transcriptomic data and cannot be validated, this could be more comprehensively characterized. Min Woo Kim et al. Nature2025 show that suppressor T cells prevent autoantigen responses via CTLA-4 and TGF-β (PMID: 39476864). As well, cDC1s are also known to promote activation of CD4+ T cells, which co-operatively support CD8+ T cell cytotoxicity (Ferris et al Nature 2020 PMID: 32788273, Espinosa-Carrasco et al. Cancer Cell 2024 PMID: 38906155). A further profiling of the regulatory T cell, as well as the broad CD4+ T cell repertoire and how it regulates neuropathology, would strengthen the specificity of these findings and provide more insight into underlying disease mechanisms.

Significance/Novelty: This study is the first to identify that cDC1s are upstream of CD8+ T cell responses in neurodegeneration. While cDC1s are well-characterized in cancer and viral infection, how they influence neurodegeneration is unclear. CD8+ T cells have recently been described to promote worsening of neurodegeneration in models of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis, and infiltrate the aging brain to promote cognitive decline. This study provides evidence that cDC1s play a role in the process of this priming and orchestrate the emergence of these responses to brain-derived antigens specifically in brain-draining lymphoid tissue. While hypotheses suggest that CD8+ T cell-mediated neurodegeneration may occur due to priming against microbial antigens or because of bystander activation. This preprint in turn suggests that brain-derived antigens are cross-presented by cDC1 to promote immunity that worsens neurodegeneration.

This insight into the role that DCs play in shaping disease course raises several questions to consider in the development of novel therapeutic strategies to treat neurodegeneration. First, given that it is now understood that tolerance to brain-derived antigens is actively maintained in the deep cervical lymph node, does altered maintenance of this tolerogenic niche by cDC1s influence pathogenic functions of lymphocytes in disease? An understanding of how cDC1-mediated antigen presentation changes with acute and chronic brain disease, as well as in aging, may identify ways that cDC1s can be therapeutically targeted to halt neurodegeneration. Second, alongside the above, the authors identify that antigen-specific priming of CD8+ T cells is enriched in the deep cervical lymph node. This calls into question whether this niche may be actively required to support chronic neurodegenerative disease pathology. CD8+ T cells often adopt a tissue-resident memory phenotype in neurodegeneration that is considered challenging to therapeutically target given its compartmentalization within the brain. Further exploration into whether this niche in the deep cervical lymph node supports maintenance and continued cytotoxicity of these CD8+ tissue-resident memory T cells could identify how these compartmentalized cells may be targeted by peripherally targeted therapies. Finally, the authors propose that antigen drainage from the brain into proximal lymph nodes facilitates priming against brain antigens. Given that chronic inflammation is proposed to precede instigation and progression of neurodegenerative disease, this finding will help frame future work investigating whether these parameters alter the dynamics of this antigen drainage to contribute to disease.

Credit: Reviewed by Jonathan Monteiro as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto. The author declares no conflict of interests in relation to their involvement in the review.