Mechanisms Regulating Chronic Immune Activation in the CNS

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Aging, neurodegeneration, persistent infection, autoimmune disease, and tumors can all trigger chronic immune activation in the CNS. Such prolonged immune states disrupt CNS barrier integrity and contribute to progressive neurological decline. Our research focuses on mechanistically defining these processes and developing therapeutic strategies that eliminate CNS pathogens while minimizing immunopathology. To model viral persistence, we use lymphocytic choriomeningitis virus (LCMV), a pathogen of both mice and humans. Infection with LCMV establishes a persistent state characterized by dendritic cell dysfunction, deletion and exhaustion of virus-specific T cells, and rapid onset of CNS viral persistence—hallmarks that are also observed during persistent viral infections in humans, including human immunodeficiency virus (HIV). We discovered that LCMV directly targets CNS barrier structures, including the meningeal sinuses, eliciting a robust local immune response. Defining how these barriers sustain antiviral immunity, and how long-term pathogen persistence alters barrier homeostasis and neurological function, is a central focus of our work. Neurodegenerative diseases activate both innate and adaptive immune pathways, which can either slow or accelerate disease progression. We defined beneficial immune pressures during tauopathy development in mice and humans. In tau transgenic mice, microglia initially slowed disease by restricting the spread of phosphorylated tau (pTau) within the CNS and circulation. Over time, however, microglia adopted a distressed antigen-presenting phenotype, acquired neuronal transcripts, and became targets of clonally expanded, resident CD8⁺ T cells. These T cells did not express canonical effector molecules such as IFNγ, TNF, or granzymes A/B/C, but instead deposited granzyme K (GZMK) onto microglia and were regulated by checkpoint proteins TIGIT and PD1—blockade of which accelerated tauopathy progression. Notably, GZMK⁺ CD8⁺ T cells also targeted microglia in pTau-rich lesions in human brains affected by aging, Alzheimer’s disease, or chronic traumatic encephalopathy. In mice, CD8⁺ T cell deletion enhanced the emergence of distressed, neuron-transcript–bearing microglia, accelerated pTau spread, and worsened neurological decline. These findings demonstrated that GZMK⁺ CD8⁺ T cells were a signature of tauopathy in both mice and humans and could potentially be harnessed to slow disease progression. Glioblastomas (GBM) are highly aggressive CNS tumors that impose major challenges on both resident and peripheral immune systems. We study GBM immunology to understand why the CNS mounts such a limited defense against these uniformly fatal tumors. We found that the GBM microenvironment is largely devoid of adaptive anti-tumor immunity and instead promotes an innate wound-healing response reminiscent of brain injury. To overcome this immunological silence, we developed transcranial therapeutic strategies to enhance meningeal immune responses against GBM. In particular, we identified specialized meningeal niches capable of supporting local humoral immunity and leveraged these sites to promote tumor control. Importantly, these findings in mice parallel the immunological deficits observed in human GBM, highlighting the potential of targeting CNS barrier immunity to improve therapeutic outcomes in patients.