Anti-CXCR3 Therapy Reduces Harmful Immune Cell Infiltration into the Brain
The immune system of the brain and body are distinct from one another, separated by the blood-brain barrier that lines blood vessels passing through the central nervous system. In health and youth, only small numbers of immune cells from the body pass in the brain, but this number increases considerably with advancing age and the presence of neurodegenerative disease. The blood-brain barrier leaks, and immune cells from the body finding their way into the brain in ever greater numbers are thought to maladaptively promote inflammation, causing dysfunction and damage in brain tissue. Here, researchers find an approach to slowing down this passage of immune cells into the brain, producing benefits in a mouse model of neurodegeneration.
CXCR3 is a well-defined chemokine receptor expressed by T cells, predominantly on activated T helper 1 (Th1)-polarized CD4+ and cytotoxic CD8+ T cells. Its canonical chemokine ligands, CXCL9, CXCL10, and CXCL11, are induced by interferon gamma (IFNγ) and are abundant during chronic inflammation. Upon homing to tissues, activated T cells amplify immune responses by secreting chemokines and cytokines such as IFNγ to facilitate cellular damage. In peripheral tissues, CXCR3-ligand interactions orchestrate T cell recruitment and infiltration into tissues, and some lines of evidence suggest a role in neuroinflammatory conditions.
We hypothesized that the CXCR3 axis is an important chemotactic gradient for brain-infiltrating T cells in tauopathy, thereby linking peripheral immune activation to tau-driven brain injury. To address this, we established an acute model of brain T cell infiltration via stereotaxic injections of recombinant IFNγ into the hippocampus. Using this model allowed us to confirm that antibody-mediated blockade of CXCR3 and genetic deletion of Cxcr3 or Cxcl10 prevented brain T cell infiltration. This confirmed that acute central nervous system injection of IFNγ could result in brain T cell infiltration and a putative role for CXCL10 and CXCR3 in this 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 major histocompatibility complex (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.