New research reveals how immune cells infiltrate the brain, influencing neurological diseases, mental health, and even behavior—reshaping our understanding of brain function and unlocking potential new therapies.
Review: The neuroimmune connectome in health and disease. Image Credit: Corona Borealis Studio / Shutterstock
Scientists are uncovering how the immune and nervous systems constantly “talk” to each other—sometimes with damaging results. In a recent review published in the journal Nature, Harvard Medical School scientists explored how this communication, known as neuroimmune interactions, can fuel brain diseases, influence behavior, and be shaped by our environment and sleep.
Immune Activity in the Brain
Growing evidence indicates that immune and brain cells interact closely, significantly affecting brain health and disease. Early research on multiple sclerosis showed that immune cells invade the brain and cause inflammation.
Now, evidence suggests this immune activity is also involved in other conditions, including Alzheimer’s and Parkinson’s diseases.
Clonally expanded CD8+ T cells have been found in the cerebrospinal fluid of Alzheimer’s patients and are known to react to proteins such as amyloid-beta. These cells have also been observed to target tau proteins in experimental models, causing damage to neurons.
In Parkinson’s disease, CD8+ T cells attack alpha-synuclein, contributing to neuron loss. Similarly, TH17 helper T cells, which produce interleukin-17 (IL-17), have been implicated in dopaminergic neuron degeneration in both Parkinson’s disease and Lewy body dementia. T cells reactive to certain proteins also worsen multiple sclerosis-related nerve damage.
However, immune cells can sometimes also support repair. Studies have shown that CNS-reactive T cells helped recover vision in optic nerve injury models. Researchers have also proposed that some ‘interoceptive’ T cells act as sensors for tissue damage and may aid healing by responding to cues within the body.
The review also discussed how immune activity alters behavior. Studies have found that xanthine from CD4+ T cells promotes stress-induced anxiety-like responses, while IL-17 from γδ T cells enhances fear-related behaviors. Additionally, inflammation in pregnant mice led to offspring with social difficulties.
Furthermore, infections and chronic stress have been linked to immune cells releasing molecules such as matrix metalloproteinase 8 (MMP8) and interleukin-6 (IL-6), which can disrupt the blood-brain barrier, affecting the brain circuits that control mood and motivation. This interaction may contribute to depression and social withdrawal during illness. These findings suggest that immune activity shapes both brain health and behavior in complex ways.
Contributing Factors
The scientists further discussed how our environment, diet, and sleep patterns shape how the immune system interacts with the brain. Microorganisms, pollutants, and dietary components can all influence this delicate connection between the brain and the immune system.
The gut microbiome is known to produce molecules that travel to the brain and affect immune cells both directly, by crossing the blood-brain barrier, and indirectly, by altering immune cells that later migrate to the brain. Studies on mice have found that changes in gut bacteria influence the T cells involved in brain inflammation, while bacterial byproducts also promote neuron repair.
In addition, diet is known to play an important part, with high salt content linked to increased inflammatory T cells and impaired cognitive function. On the other hand, tryptophan from food regulates astrocytes, which play a role in neuroimmune balance.
The review stressed the importance of sleep for brain health and immunity. Melatonin is known to influence CD4+ T cell polarization, while hypocretin suppresses inflammatory monocyte production, which is linked to atherosclerosis. Sleep loss can trigger inflammatory responses, worsen heart disease, and contribute to autoimmune conditions like narcolepsy. Disrupted sleep can also fuel long-term neuroimmune dysfunction.
Pollutants can have similar disruptive effects. Studies have found that chemical pollutants can activate the aryl hydrocarbon receptor (AHR) in brain cells, triggering inflammation and emphasizing the impact of environmental toxins on brain health.
These findings highlight the role of everyday exposures — from the food we eat to the air we breathe and how well we sleep — in subtly shaping brain-immune communication.
Studying the Brain-Immune Connection
Understanding the brain-immune connection requires cutting-edge tools to study how cells communicate. The review explored some of these new methods, such as Rabies Barcode Interaction Detection with Sequencing (RABID-seq), which labels and tracks specific immune-neuron interactions.
The study also discussed other technologies such as BRIC-seq and MAP-seq, which use viral barcoding to trace neuroimmune connections, and LIPSTIC, a labeling technique for studying in vivo immune-neuron interactions. These tools allow researchers to identify how immune cells and neurons communicate in living tissues.
In addition, optogenetics and bioelectronic implants allow scientists to manipulate neuroimmune circuits, stimulating specific neurons and tracking how they influence immune responses.
Furthermore, the mapping of immune cell behavior within the brain is also advancing, including various spatial profiling tools that track cell locations and time-sensitive sequencing methods that record rapid cellular changes. The researchers discussed how combining these approaches offered a clearer view of how immune and brain cells influence each other in health and disease.
Future Research
The researchers believe that current studies in the field aim to map the entire neuroimmune connectome and explore this web of interactions. They seek to understand how short-lived immune reactions may cause long-lasting changes in brain function and whether past immune challenges can leave an imprint on neuroimmune circuits, affecting behavior and neurological health over time.
Scientists hope decoding these patterns will lead to therapies that balance inflammation, promote repair, and protect mental health. However, the complexity of these networks poses a significant challenge, which will require both advanced tools and computational models to unravel their full scope.