Meningeal and infiltrating T-cells are associated with repetitive head trauma and tau-mediated neurodegeneration in chronic traumatic encephalopathy

Central nervous system (CNS) associated T-cells are present in the meninges and perivascular spaces of healthy brain tissue, but their recruitment into the brain parenchyma is increased by inflammation and hyperphosphorylated tau (p-tau) accumulation. Chronic traumatic encephalopathy (CTE) is a progressive tauopathy associated with exposure to repetitive head impacts (RHI) and definitively diagnosed by the presence of a pathognomonic perivascular p-tau lesion, most commonly at the sulcal depths of the dorsolateral frontal cortex (DLF). Exposure to RHI and CTE is associated with substantial neuroinflammation; however, the involvement of T cells is unknown. Here, we used post-mortem human brain tissue to assess T-cell accumulation in the DLF of 58 individuals exposed to RHI, including 19 with neuropathologically verified Low CTE (stage I-II), 23 with neuropathologically verified High CTE (stage III-IV), and 16 without CTE, as well as 18 controls unexposed to RHI and without CTE. Multiplex immunofluorescence was utilized to label T-cells, microglia, p-tau, and synapses in the leptomeninges, sulcal gray matter, crest gray matter, and white matter. We found that infiltrating T-cells were significantly increased in the sulci across all groups compared to controls, with distinct subtypes in RHI without CTE, compared to Low or High CTE. In addition, T-cell infiltration correlated with the duration of RHI, as measured by years of sports play, and synaptic loss. Meningeal and infiltrating T-cells were elevated in sulci with p-tau depositions and spatially related to MHC2 expressing cells. Meningeal T-cells were also significantly correlated with a younger onset of behavioral symptoms. These data suggest that T-cells may play a role in the chronic inflammation and degeneration associated with RHI and CTE.