Bidirectional Regulatory Mechanisms of T cell-microglia Interactions in Cerebral Ischemic Disease: Molecular...

Cerebral ischemic diseases, such as ischemic stroke (IS) and vascular dementia (VaD), are major causes of neurological disability and mortality. Neuroinflammation acts as a pivotal driver of secondary brain injury, mediated by intricate bidirectional interactions between peripheral T cells and central nervous system (CNS)-resident microglia. This review delineates the molecular mechanisms underlying T cell-microglia crosstalk in cerebral ischemia, emphasizing their dual roles in exacerbating neurotoxicity and promoting repair. Direct interactions involve antigen presentation via MHC-TCR engagement and co-stimulatory checkpoints (e.g., CD80/CD86-CD28, PD-L1-PD-1), which regulate T cell activation and microglial polarization. Direct signaling through cytokines (IFN-γ, IL-4, IL-17, IL-10) further modulates microglial phenotypes: Th1/Th17 cells drive pro-inflammatory M1 polarization via STAT1/NF-κB pathways, while Tregs/Th2 cells induce anti-inflammatory M2 states through STAT6/SMAD signaling. Spatial transcriptomics and single-cell omics reveal spatiotemporal dynamics of these interactions, identifying STAT1/STAT6 imbalance as a critical determinant of neuroinflammatory outcomes. Advanced methodologies, including two-photon intravital microscopy and microfluidic blood-brain barrier (BBB) models, enable real-time visualization of immune cell trafficking and synaptic communication. Therapeutically, targeting immune checkpoints (CTLA-4, PD-1) or cytokine pathways (e.g., IL-4 mimetics) shows promise in recalibrating neuroimmune responses. However, challenges such as blood-brain barrier impermeability to biologics and interspecies immune heterogeneity necessitate innovative delivery strategies. This review integrates molecular, cellular, and technological insights to propose a framework for precision immunomodulation. By elucidating context-dependent signaling nodes and leveraging emerging tools, the study underscores the potential of harnessing T cell-microglia crosstalk to mitigate neuroinflammation and enhance neural repair, offering transformative avenues for stroke and dementia therapy.