Several routes exist for immune cells and neurons to communicate, though T cells rarely come in direct contact with neural tissue. This communication can happen as cerebrospinal fluid (CSF) flows from the space surrounding blood vessels deep in the brain into neural tissue and back out again. As an animal learns new information, changing neural circuits can release signals to which the immune system responds. The immune system in the meninges, the spongy membranes that separate neural tissue from the skull, also monitors CSF coming from the brain for signs of infection or injury.
The meninges’ innermost layer, the pia mater, lines the perimeter of the brain, separating neural tissue from the surrounding fluid and tissue. But gaps in the thin, fibrous tissue allow blood vessels to extend deep into the brain.
Along blood vessels in the brain, a tightly packed layer of endothelial cells, along with projections, or “feet,” from astrocytes collectively make up the blood-brain barrier, which prevents blood from entering the organ. But CSF that sits in the space between the pia mater and upper layers of the meninges flows down around the endothelium-lined blood vessels.
As arteries pulse with each beat from the heart, CSF pushes into the astrocyte feet through AQP4 water channels. This CSF can carry signals from the immune system such as cytokines IL-17, IL-4, and interferon gamma that may also talk directly with neurons.
Cytokines can also trigger astrocytes to release molecules such as brain-derived neurotrophic factor (BDNF), influencing learning, memory, and sociality.
Once in the brain, the CSF mixes with extracellular fluid from neuronal tissue, sweeping up cellular waste excreted along with any toxins, pathogen-derived antigens, and debris formed as part of normal neural rewiring. This fluid is then pushed out of the brain through astrocyte feet into the perivascular space, where it can interact with gamma delta T cells. Those T cells may then respond by releasing cytokines such as IL-17 that can move right back into the brain, although this has yet to be shown.
The CSF is then channeled to the lymphatic vessels in the meninges and flushed to lymph nodes in the neck, where more T cells are waiting to scan the fluid and respond.
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