Blas Couto and al.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder with 4-repeat (R) tau protein deposition. The substantia nigra (SN) and midbrain tegmentum nuclei (MBT) are consistently affected. To evaluate cytotoxic T-cell response, serial sections spanning 120 microns of the SN were consecutively immunostained for phosphorylated tau (AT8) or α-synuclein, cytotoxic T-cell marker and microglia marker HLA-DR in 9 patients with PSP, 10 with PD, and 6 healthy controls. CD8 lymphocyte cell counts, and microglial activation were increased in the SN of PSP compared to PD and controls. T-cell/neuron contact was observed in PSP. In multivariate models, CD8 counts were not predicted by disease duration, younger age at death, and by the amount of p-tau pathology. SN and midbrain tegmentum showed more CD8 cells than the cortex. The presence of more prominent nigral cytotoxic T-cell response in PSP than in PD supports the notion that the common p-tau neuropathology in PSP might have potential relationships with autoimmune mechanisms.

Javier María Peralta Ramos and al.

The authors used high-dimensional single-cell mass cytometry  to find a unique immunometabolic signature in circulating CD4⁺ T cells preceding symptom onset in individuals with familial AD, featured by the elevation of CD38 expression. Using female 5xFAD mice, a mouse model of AD, they show that treatment with an antibody directed to CD38 leads to restored metabolic fitness, improved cognitive performance, and attenuated local neuroinflammation. Comprehensive profiling across distinct immunological niches in 5xFAD mice, reveals a high level of disease-associated CD4⁺ T cells that produce IL-17A in the dural meninges, previously linked to cognitive decline. Targeting CD38 leads to abrogation of meningeal T_H17 immunity and cortical IL-1β, breaking the negative feedback loop between these two compartments. 

Kirit Singh and al.

The authors investigated whether peripherally infused non-antigen specific autologous lymphocytes (ALT) could accumulate in intracranial tumors. They observed that non-specific autologous CD8+ ALT cells can indeed accumulate in this context, despite endogenous T cell sequestration in bone marrow. Rates of intratumoral accumulation were markedly increased when expanding lymphocytes with IL-7 compared to IL-2. Pre-treatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and non-tumor-specific T cell-dependent immunotherapies against orthotopic murine and human xenograft gliomas. Mechanistically, increased VLA-4 on mouse and human CD8+ T cells was observed following IL-7 expansion, with increased transcription of genes associated with the migratory integrin CD9.

Rui Xiong and al.

Maternal separation (MS), a chronic stress event in early life, impairs myelination in the prefrontal cortex (PFC) and leads to cognitive disorders. Here, the authors show that peripheral CD4+ T cells play an essential role in mediating the destructive effects of MS on medial prefrontal cortical (mPFC) myelination and cognitive functions in mice. Offspring mice with MS experience (MS mice) exhibited an increase in CD4+ T cells and xanthine levels in peripheral blood and a severe deficit in mPFC-dependent cognitive functions such as working memory, social interaction, and anxiety/depression emotion regulation, along with a decrease in oligodendrocyte precursor cells (OPCs) and oligodendrocytes (Ols) in the mPFC. These phenotypes were rescued upon treatment with an antibody neutralizing peripheral CD4+ T cells. Rag1−/− immunodeficient mice receiving transplantation of CD4+ T cells isolated from the peripheral blood of MS mice showed similar phenotypes as observed in MS mice. Immunofluorescence staining revealed a rich expression of adenosine receptor A1 (A1) in OPCs in the mPFC, and the A1-expressing OPCs decreased in Rag1−/− mice receiving CD4+ T cell transplantation.

Min Zhang and al.

Herpes simplex encephalitis (HSE) caused by HSV-1 is the most common non-epidemic viral encephalitis, and the neuropathogenesis of HSE remains elusive. This work describes a 3D human neurovascular unit (NVU) model that allows to explore the neuropathogenesis of HSE in vitro. This model is established by co-culturing human microvascular endothelial cells, astrocytes, microglia and neurons on a multi-compartment chip. Upon HSV-1 infection, this NVU model exhibited HSE-associated pathological changes, including cytopathic effects, blood-brain barrier dysfunction and pro-inflammatory cytokines release. Besides, significant innate immune responses were observed with the infiltration of peripheral immune cells and microglial activation. Transcriptomic analysis revealed broadly inflammatory and chemotactic responses in host cells. Mechanistically, we found HSV-1 could induce severe suppression of autophagic flux in glial cells, especially in microglia.