T Cells Coordinate with Microglia in the Alzheimer's Brain
The brain is immune privileged and has its own immune system separated from that of the rest of the body by the blood-brain barrier. It isn't true that T cells of the adaptive immune system are never found in the brain, however. There are ways in, and as researchers show here, T cells do play a role in coordinating the immune defense against issues such the excessive protein aggregation characteristic of neurodegenerative conditions such as Alzheimer's disease. There is an increasing focus on immune system dysfunction and chronic inflammation in the aging of the brain and onset of neurodegeneration. Exerting greater control over cells that have become overly inflammatory is an important goal in the research community, and hence the interest in finding existing mechanisms whereby that might be occurring.
Microglia are immune cells in the brain responsible for clearing beta-amyloid plaques. As Alzheimer's disease progresses, microglia can lose their capacity to remove these plaques and instead produce inflammatory mediators that may accelerate beta-amyloid plaque progression. Researchers have found that accumulating another subtype of immune cells, called CD8+ T cells, is essential to slow this process by interacting with microglia. This interaction, in turn, was important to limit beta-amyloid burden and preserve memory capabilities in a mouse model of the disease.
To understand how T cells were delaying symptom progression in their Alzheimer's disease model, researchers searched for the most abundant molecular interaction between CD8+ T cells and the microglia. They found a protein on the surface of CD8+ T cells, CXCR6, interacts with the protein CXCL16 expressed by microglia. The two surface proteins, CXCR6 and CXCL16, essentially performed a handshake between the two cells, communicating in both directions. Just like the firmness of a human handshake can convey information, so can the interaction of these two proteins on the outside of their respective cells.
The scientists determined how the handshake occurs and delays the onset of Alzheimer's disease-related pathologies. The CD8+ T cells first move next to the microglia, which are localized next to the beta-amyloid plaques. Then, the CD8+ T cells use the handshake to signal to the microglia to stop causing uncontrolled inflammation, which, in turn, slows plaque growth and symptoms in the mouse models. When the scientists deleted the gene for the CD8+ T cell's protein CXCR6, the mice developed worse Alzheimer's disease-related symptoms. This effect was partially because the CD8+ T cells without CXCR6 failed to accumulate in the brain near the microglia or plaque site. These cells also did not acquire the appropriate suppressive function. Thus, disrupting the CD8+ T cell's ability to perform the handshake prevented its protective effect against Alzheimer's disease symptoms.