Spilling the T: T cells in tauopathy mechanisms, disease progression, and therapeutic horizons

Primary and secondary tauopathies are major causes of dementia characterized by the abnormal accumulation of microtubule-associated protein tau. Tau aggregation initiates neuronal dysfunction and death, while despite the distinct and pathological features of individual tauopathies, accumulating evidence shows that these disorders converge on shared mechanistic pathways marked by chronic inflammation and progressive neuronal loss. The innate immune response has been extensively studied in this context, yet the contribution of the adaptive immune system, particularly T cells, has only recently gained attention. In this review, we examine emerging evidence for adaptive immune involvement in tauopathies, including mechanisms that drive T cell activation and infiltration into the central nervous system, their effector functions once within the parenchyma, and how these responses interact with innate immune signaling. We also highlight potential therapeutic strategies aimed at modulating adaptive immunity in primary and secondary tauopathies. Current findings suggest that tau accumulation and glial-driven neuroinflammation creates an environment that promotes the activation and recruitment of effector T cells into the tauopathy brain. Importantly, blocking or reshaping the T cell responses shows promise for mitigating neurodegeneration, highlighting the adaptive immune system as a potential therapeutic target.