CNS Neurosci Ther. 2026 Aug;32(8):e71092. doi: 10.1002/cns.71092.
ABSTRACT
BACKGROUND: Stroke is a leading cause of disability and mortality worldwide, with ischemic stroke accounting for approximately 87% of all cases. Despite advances in reperfusion therapy, effective treatments targeting secondary neuroinflammation remain limited. Accumulating evidence indicates that γδ T cells, particularly through the production of interleukin (IL)-17, contribute to ischemic brain injury. As the intestine represents a major reservoir of γδ T cells, brain-gut communication may connect intestinal immune alterations with post-stroke neuroinflammation. This review examines the role of γδ T cells in ischemic stroke from the perspective of the brain-gut axis.
METHODS: We synthesized current mechanistic evidence from experimental, translational, and clinical studies concerning γδ T-cell activation and recruitment after ischemic stroke. Particular attention was given to IL-17-mediated neuroinflammation, intestinal barrier dysfunction, gut microbiota dysbiosis, and bidirectional immune communication between the ischemic brain and the intestine.
RESULTS: Following ischemic stroke, γδ T cells are activated and recruited to the injured brain, where their production of IL-17 promotes neuroinflammation, blood-brain barrier disruption, and secondary tissue injury. Concurrently, cerebral ischemia induces autonomic, immune, and metabolic disturbances that alter the gut microbiota and compromise intestinal barrier integrity. These changes may facilitate microbial product translocation and systemic inflammation, thereby amplifying cerebral inflammatory responses. Gut-resident γδ T cells may participate in this process by regulating mucosal immunity and IL-17-associated inflammatory signaling. Together, these mechanisms may establish a self-reinforcing brain-gut injury cycle. However, direct evidence defining the contributions, trafficking patterns, and functional heterogeneity of specific intestinal γδ T-cell subsets in ischemic brain injury remains limited.
CONCLUSIONS: γδ T cells may serve as important immunological mediators linking intestinal dysfunction to neuroinflammation after ischemic stroke. Therapeutic strategies targeting γδ T-cell activation, IL-17 signaling, intestinal barrier disruption, or gut microbiota dysbiosis may help interrupt the brain-gut injury cycle. Future studies integrating lineage tracing, single-cell and spatial profiling, and tissue-specific interventions are required to distinguish the roles of brain-infiltrating and gut-resident γδ T-cell subsets and facilitate the clinical translation of brain-gut axis-based therapies.
PMID:42610631 | DOI:10.1002/cns.71092