Lymphocytes have rarely been considered as players in brain immunity because they cannot cross the blood-brain barrier. In recent years, however, it has become clear that the adaptive immune system, in which B and T cells play an important role, is active in the brain and may play a key role in neuronal cell death in old age. Now, in the journal Nature, Chen and colleagues describe the specific role of T cells in neurodegeneration in Alzheimer's disease. Their findings suggest that adaptive immunity in the brain needs to be looked at in a completely new way and represents a potentially significant therapeutic target.
Alzheimer's disease is characterized by the accumulation of extracellular amyloid-β (Aβ) protein and intracellular aggregates of tau protein. Although both proteins are considered hallmarks of the disease, brain atrophy correlates virtually only with tau accumulation but not with Aβ deposition. The paper specifically addresses the question of whether tau aggregates trigger a specific immune response in surrounding cells, which then leads to neuronal degradation.
The authors used mouse models of Alzheimer's disease that have either Aβ deposition or tau aggregation, but not both together. The scientists focused on lymphocytes, which they isolated from the brains of the mice and examined them by single-cell RNA sequencing (used to identify cell types based on the genes expressed in them).
What was particularly striking was that there were significantly more T lymphocytes in the brains of the tau mice than in those with Aβ deposits. In particular, cytotoxic T cells (CD8-positive 'killer cells') could be detected, and their numbers correlated not only with tau deposits but also with neurodegeneration. However, the cells showed signs of exhaustion (their chronic activation appears to convert them to a dysfunctional state, causing them to lose their normal capabilities).
Chen and colleagues confirmed the findings collected in mice using brain slices from patients who had died of Alzheimer's disease. They found that the number of T cells increased in the superior frontal gyrus of the frontal lobe, whereas in the tau mouse, lymphocytes were particularly detectable in the hippocampus and entorhinal cortex of the temporal lobe. All of these structures are closely linked to learning and memory.
T cells are activated when their receptor binds to an antigen. This is usually a fragment of a foreign protein or a modified fragment of one of their own proteins presented by another cell. Examination of immune cells normally resident in the brain revealed that in Alzheimer's mice, microglia had adopted a disease-associated state and were in close proximity to CD8-positive T cells in brain slices from tauopathy mice. The authors then demonstrated in cell culture experiments that culturing microglia and T cells together with a foreign antigen resulted in a marked increase in T cells.
Chen et al. therefore hypothesized that microglia and T cells together promote brain atrophy in response to tau. To test this hypothesis, they administered a drug, or antibody, known to cause microglia and T cell death, respectively, to mice with tauopathy. When the drug was administered at a time when neurodegeneration was already developing, both treatments resulted in a marked decrease in brain atrophy and a reduction in signs of the deleterious effects of tau. In addition, after depletion of T cells, the animals' performance in various memory and learning tests was virtually normal.
In terms of potential therapies, it is probably not possible to remove entire immune cell populations in humans. However, modulating the unwanted immune response is an alternative. For this purpose, the researchers injected mice with tauopathy with anti-PD-1 antibodies, which is already used clinically in cancer immunotherapy. This treatment triggers a chain reaction that leads to activation of T cells. Short-term anti-PD-1 treatment increased the proportion of regulatory T cells that inhibit activated T cells. Long-term anti-PD-1 treatment then also reduced neurodegeneration and the amount of tau deposition. However, it would still need to be determined whether anti-PD-1 treatment affects cognition before a similar approach could be tested in humans.
In addition, other questions remain unanswered: are the T cells new to the brain or are they derived from cells that perform physiological tasks ? What is the exact mechanism of antigen presentation in the brain ? Normally, antigen presentation and T cell activation occur in the lymph nodes. Chen and colleagues' work specifically points to the role of microglia - a type of cell that is less effective than other cell types in antigen presentation. Alternatively, macrophages, which are found in the meninges, could help with antigen presentation. A third possibility would be that other cells present antigens to regulatory and CD8+ T cells.
But what antigens do the T cells recognize in tauopathy ? They could be viral antigens, for example, because T cells have been shown to bind them in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease. Also, large epidemiological studies point to viral antigens in neurodegeneration. In addition, T cells are known to recognize a disease-promoting protein (α-synuclein) and may have an important function in Parkinson's disease. Therefore, the immunology of neurodegeneration will be of great importance in the study and treatment of neurodegeneration in the coming years.
References:
Chen X, Firulyova M, Manis M, ... , Ulrich JD, Holtzman DM (2023) Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature 615:668
Guldner ICH, Wyss-Coray T (2023) Activated immune cells drive neurodegeneration in an Alzheimer's model. Nature 615:588
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