The role of γδ T cells in the pathogenesis of Alzheimer's Disease

Alzheimer’s disease (AD) is a severe progressive neurodegenerative disorder representing the most common cause of dementia. Nowadays more than 45 million people worldwide are affected by AD, and this number will increase because of the increase in life expectancy. At the neuropathological level, the hallmarks of this disorder are deposition of beta amyloid (Aβ) peptides and neurofibrillary tangles (NFTs) formation. Vascular inflammation and a dysfunctional blood-brain-barrier (BBB) have been also implicated in the pathogenesis of AD. Moreover, circulating leukocyte subpopulations, including T cells, have been identified in the brains of patients with AD and in their corresponding animal models. The canonical T cells have a T cell receptor (TCR) composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. However, there is also a noncanonical population of T lymphocytes harboring γ (gamma) and δ (delta) TCR chains. γδ T cells are mainly divided into two distinct groups based on their cytokine production: IL-17 producers and IFN-γ producers, and they might play different roles in inflammatory conditions. Previous studies have shown that γδ T cells are involved in neurodegenerative disorders like multiple sclerosis (MS) and autoimmune rheumatic diseases. However, their role in the pathogenesis of AD is still poorly understood. Our main goal was to characterize the impact of γδ T cells on disease pathogenesis in animal models of AD. In this study, we reveal that γδ T cells begin to infiltrate the meninges and brain during the early stages of the disease in 3xTg-AD mice, which develop both amyloid and tau pathologies. In 3xTg-AD mice deficient for γδ T cells, we observed memory improvement and reduced neuroinflammation, Aβ deposition and tau hyperphosphorylation compared to control animals. We also found that infiltrating γδ T cells displayed transcriptional signatures of highly activated IL-17-producing cells potentially promoting neuronal damage. Indeed, IL-17 blockade in vitro dramatically reduced neuronal death induced by γδ T cells, suggesting activated γδ T cells contribute to neurodegeneration in AD. Importantly, IL-17 blockade in vivo ameliorated the neuropathological hallmarks of AD, confirming a role for IL-17+ γδ T cells in the pathogenesis of this disease. Our results therefore demonstrate that the activation of γδ T cells induces major pathological features of AD, suggesting that interfering with γδ T cell activity may offer a novel therapeutic approach for neurodegenerative diseases.