Peripheral CXCR3 blockade mitigates T cell infiltration and neurodegeneration in a mouse model of tauopathy.

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.