Midbrain cytotoxic T cells as a distinct neuropathological feature of progressive supranuclear palsy

Abstract

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by four-repeat (4R) tau protein deposition. The substantia nigra (SN) and midbrain tegmentum nuclei (MBT) are consistently affected. Lymphocyte infiltrates are scarce in the brains of patients with neurodegenerative diseases, although a few reports have described their presence in the α-synucleinopathy Parkinson's disease (PD). To evaluate the cytotoxic T-cell response, serial sections spanning 120 μm of the SN were immunostained consecutively for phosphorylated tau (p-tau, AT8) or α-synuclein, cytotoxic T-cell marker and microglia marker HLA-DR. Sections were analysed with stereology software in 9 patients with PSP, 10 with PD and 6 healthy controls. We semiquantitatively scored CD8-positive cells in further brain regions. CD8 lymphocyte cell counts and microglial activation in the SN were higher in PSP than PD and controls. Furthermore, T-cell/neuron contact was observed in PSP. In multivariate models, CD8 counts were not predicted by disease duration, younger age at death or the amount of p-tau pathology. The SN and midbrain tegmentum showed more CD8 cells than the cortex. A more prominent nigral cytotoxic T-cell response in PSP than PD supports the suggestion that p-tau neuropathology in PSP might have potential relationships with autoimmune mechanisms.

Keywords: T-lymphocyte; inflammation; neuropathology; progressive supranuclear palsy; tau.

Figure 1

Differences in CD8-cell counts between conditions and regions. Density of CD8 cell infiltrates in the substantia nigra (SN) of progressive supranuclear palsy (PSP), Parkinson's disease (PD) and control (CO) subjects (A). CD8 cells in PSP and PD according to disease duration subgroups: benign (PSP >8 years, PD >12 years) and malignant (PSP <7 years, PD <11 years) courses (B). High magnification of the midbrain in case PSP-6 showing (blue-stained) CD8 infiltrates including lymphocytes in close proximity to the neuronal cell membrane (C). Semiquantitative scoring (0–3; n/a = not available) and heat mapping of parenchymal and perivascular CD8-cell-infiltrates in PSP-specific regions for nine PSP cases and five controls; note that only five control cases where most of the brain regions were available were included (D). CD8-cell count in red nucleus/superior cerebellar peduncle (RN/SCP) and midbrain tegmentum (MBT) in PSP (E); note that 15 samples were used for RN/SCP, since three cases had bilateral tissue available, which were all counted. CD8-cell infiltrates in the SN subregions annotated for PSP and PD (F). Note that in subregions, higher values than the mean of the summarized data plotted for the whole SN can be observed. STN = subthalamic nucleus; STR = striatum; GP = globus pallidus; MOT = motor cortex.

Figure 2

Regional distribution of CD8-positive cells. Immunohistochemistry for CD8-positive cells (brown) in control (CO) (A, D, G, J and M) and two cases with progressive supranuclear palsy (PSP) (B, C, E, F, H, I, K, L, N and O) in the substantia nigra (A–C), red nucleus/superior cerebellar peduncle (D–F), subthalamic nucleus (G–I), globus pallidus (J–L) and motor cortex (M–O). Note the more prominent CD8 cells in PSP, including CD8 cells surrounding neurons (B). Arrowheads indicate parenchymal and arrows perivascular CD8 cells. Scale bar in A = 120 μm for all images except B, where it represents 15 μm.

Figure 3

Microglial load under different conditions. Mean HLA-DR (microglia) immunoreactivity area in the substantia nigra (SN) of progressive supranuclear palsy (PSP), Parkinson's disease (PD) and control (CO) samples (A). Mean microglia immunoreactivity area in SN according to disease duration subgroups: benign (PSP >8 years, PD >12 years) and malignant (PSP <7 years, PD <11 years) (B). Mean microglia immunoreactivity area in SN subregions of PSP and PD, for microglia detection (C). Note that in subregions, higher values than the mean of the summarized data plotted for the whole SN can be observed.