2026-09-28 ワシントン大学セントルイス校
＜関連情報＞
- https://source.washu.edu/2026/09/blocking-immune-cells-path-into-brain-limits-neurodegeneration/
- https://www.cell.com/neuron/fulltext/S0896-6273(26)00681-1
- https://www.nature.com/articles/s41593-026-02427-5
- https://medibio.tiisys.com/107812/
末梢CXCR3阻害は、タウオパチーのマウスモデルにおけるT細胞浸潤および神経変性を軽減する Peripheral CXCR3 blockade mitigates T cell infiltration and neurodegeneration in a mouse model of tauopathy
Joshua T. Emmerson ∙ Hao Hu ∙ Vivek Savani ∙ … ∙ Rudolph E. Tanzi ∙ Jason D. Ulrich ∙ David M. Holtzman
Neuron Published:September 28, 2026
DOI:https://doi.org/10.1016/j.neuron.2026.08.030
Highlights
- Delivery of IFNγ into the brain provokes CXCR3-CXCL10-dependent T cell infiltration
- Antibody-mediated blockade of CXCR3 blocks T cell infiltration in tauopathy
- Reduced T cell infiltration mitigates tau-mediated neurodegeneration in vivo
- CXCR3 blockade reduces Th1 CD4 T cells and increases CD8 T cell terminal exhaustion
Summary
Chemokine receptor CXCR3 mediates T cell recruitment into inflamed tissues, but its role in tauopathies is unclear. Here, we show that hippocampal injection of interferon-γ (IFNγ) acutely triggers CXCL10 upregulation and brain parenchymal T cell infiltration. Genetic deletion or antibody-mediated blockade of CXCR3 prevented IFNγ-induced T cell infiltration. In a mouse model of tauopathy and neurodegeneration, chronic systemic anti-CXCR3 treatment markedly reduced parenchymal CD4+ and CD8+ T cell accumulation, attenuated neurodegeneration, and improved aspects of cognition. CXCR3 blockade decreased microglial MHC-II expression without broadly suppressing classical disease-associated inflammatory phenotypes. Single-cell RNA sequencing and flow cytometry further revealed a reduction in the proportion of activated CD4+ T cell populations and elevated CD8+ T cell terminal exhaustion in the brain. These findings identify CXCR3-dependent chemotaxis as a critical signaling pathway for subtypes of T cells linked to tau-mediated neurodegeneration and highlight CXCR3 blockade as a potential disease-modifying therapeutic strategy for tauopathies.
末梢樹状細胞によるCD8 + T細胞のプライミングは、タウ介在性神経変性を悪化させる Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration
Hao Hu, Peter Bor-Chian Lin, Carisa Zeng, Yongyi Li, Megan E. Bosch, Joshua T. Emmerson, Prabal Sharma, Ray A. Ohara, Wendy Dong, Tong Wu, Siling Du, Wenqing Gao, Hong Jiang, Liya Yuan, Xin Bao, Shasha Li, Anthony N. Vomund, Petra Erdmann-Gilmore, Yichen Gu, Miwei Hu, Jonathan Nulman, Timothy M. Miller, Wayne M. Yokoyama, Cheryl F. Lichti, … David M. Holtzman
Nature Neuroscience Published:03 September 2026
DOI:https://doi.org/10.1038/s41593-026-02427-5
Abstract
Alzheimer’s disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8+ T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8+ T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8+ T cell infiltration and glial activation. The remaining CD8+ T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8+ T cell accumulation in the brain and tau-mediated neurodegeneration.
