Basic Science and Pathogenesis.

Background: T-cell infiltration into the brain parenchyma is associated with hyperphosphorylated tau (p-tau) accumulation in neurodegenerative diseases. Chronic traumatic encephalopathy (CTE) is a progressive tauopathy caused by exposure to repetitive head impacts (RHI). CTE is defined by the perivascular accumulation of p-tau at the cortical sulcal depths and can be stratified into mild and severe pathological stages. RHI exposure and CTE are associated with progressive microglial inflammation, but the involvement of T cells is unknown.

Method: The dorsolateral frontal cortex from 76 brain donors in the UNITE/ BU ADRC brain bank was analyzed, all men (age 30-80 yrs), including 19 with mild CTE (stage 1-2), 24 with severe CTE (stage 3-4),18 with RHI exposure without CTE, and 19 without RHI exposure or neurodegenerative disease (Table 1). Years of football served as a proxy for the duration of RHI. Multiplex immunofluorescence for T-cells (CD8 1:20, CD4 1:100), endothelial cells (CD31 1:200), microglia (iba1 1:500, MHC2 1:500), and p-tau (AT8 1:500) were used. Synaptic markers (PSD95 1:100, Gephyrin 1:200, VGlut 1:1200, VGat 1:1500) were used on adjacent tissue sections to assess synaptic loss. Four regions were annotated: leptomeninges, sulcus (gray matter (gm) in bottom third of gyrus), crest (gm in top third of gyrus), and white matter. Slides were digitally scanned, and HALO software was used to quantify T-cell numbers and spatial relationships. ANCOVA with posthoc Bonferroni corrections were performed for between group analyses; multivariate linear correlations were utilized for associations between T-cells and other markers or RHI exposure, all using age as a covariate.

Result: Infiltrating T-cells were significantly increased at the sulcus in RHI, mild, and severe CTE, with distinct subtypes predominating in RHI and CTE. In addition, T-cells were correlated with the duration of RHI exposure and synaptic loss. Meningeal and infiltrating T-cells were notably elevated in p-tau positive sulci (Fig. 1). Finally, T-cells were spatially related to CNS-associated macrophages expressing MHC2, including cortical microglia and meningeal macrophages (Fig. 2).

Conclusion: These data suggest an adaptive immune T-cell response occurs with RHI exposure, which might be microglia mediated and contribute to tau neurodegeneration in CTE.