How Brain Chemicals Control Immunity
A groundbreaking study revealed an unexpected dialogue between the immune and nervous systems, demonstrating how dendritic cells and T-cells communicate using the neurotransmitter serotonin.
Explore DiscoveryIn 2005, research revealed an unexpected form of communication within our immune system—the transmission of the neurotransmitter serotonin between dendritic cells and T-cells at specialized junctions called immune synapses 8 .
This discovery bridged the historically separate fields of immunology and neuroscience, suggesting that the same chemical signals that regulate our mood also play a crucial role in directing our immune defenses 8 .
The immune synapse, once thought to be primarily a platform for physical receptor interactions, now appears to support a more complex, rapid-fire chemical signaling system that shares striking similarities with neuronal synapses 8 .
This novel signaling mechanism may explain observed links between psychological stress, depression, and immune dysfunction, while also shedding light on how commonly used antidepressants that target serotonin uptake might inadvertently affect our body's ability to fight disease and maintain immune balance 8 .
The immune synapse is a specialized junction that forms when a dendritic cell—a specialized antigen-presenting cell—encounters and activates a T-cell. This intimate contact allows for the precise exchange of information necessary to mount an adaptive immune response 8 .
At this synapse, key recognition molecules and signaling proteins become organized into specific patterns that facilitate communication between cells 8 .
Serotonin (5-hydroxytryptamine or 5-HT) is traditionally known as a neurotransmitter that regulates mood, appetite, and sleep. Beyond its functions in the central nervous system, serotonin also serves as an important inflammatory mediator released by platelets and mast cells at sites of tissue injury 8 .
The 2005 discovery that serotonin also acts as an immune messenger between cells of the adaptive immune system revealed a previously unknown layer of complexity in both neurological and immunological regulation 8 .
Dendritic cell identifies antigen
Cells form specialized junction
Serotonin transmission occurs
T-cell initiates immune response
The research team employed multiple sophisticated techniques to unravel the novel serotonin signaling pathway between immune cells 8 :
Bone marrow-derived dendritic cells (BMDCs) were cultured from mouse bone marrow with GM-CSF and IL-4 for 5 days, while T-cells were purified from mouse spleens and activated 8 .
RT-PCR was used to detect expression of serotonin transporters (SERT) and synthesis enzymes (TPH-1) in both dendritic cells and T-cells 8 .
Antibodies against SERT and CD11c (a dendritic cell marker) helped localize the serotonin transporter within cells 8 .
Dendritic cells were tested for their ability to take up serotonin from their environment 8 .
This sensitive technique directly measured the calcium-dependent release of serotonin from dendritic cells 8 .
These cells actively take up serotonin from their environment, with uptake inhibited by the antidepressant fluoxetine 8 .
Surprisingly, T-cells were found to express tryptophan hydroxylase (TPH-1), the rate-limiting enzyme in serotonin synthesis 8 .
The neurotransmitter was stored in LAMP-1+ vesicles within dendritic cells and released via calcium-dependent exocytosis 8 .
Released serotonin was shown to reduce cAMP levels in T-cells, potentially influencing their activation state 8 .
| Reagent | Function | Application in Study |
|---|---|---|
| GM-CSF & IL-4 | Cytokines that promote dendritic cell differentiation | Generation of bone marrow-derived dendritic cells 8 |
| Fluoxetine | Selective serotonin reuptake inhibitor (SSRI) | Blocking serotonin uptake to study transporter function 8 |
| Concanavalin A | T-cell mitogen | Activating T-cells to induce serotonin synthesis 8 |
| Anti-SERT Antibody | Binds specifically to serotonin transporter | Localizing SERT expression in dendritic cells 8 |
| LPS | Toll-like receptor agonist | Maturing dendritic cells to study activation effects 8 |
The investigation followed a logical progression to establish each component of the novel signaling pathway 8 :
Characterizing serotonin machinery expression
Visualizing transporter localization
Measuring functional uptake
Demonstrating regulated release
Assessing functional consequences
This discovery fundamentally altered our understanding of cross-talk between body systems. The finding that immune cells use neurotransmitter signaling suggests possible mechanisms for well-documented but poorly understood phenomena such as stress-induced immunosuppression and the increased prevalence of autoimmune conditions in patients with mood disorders 8 .
The research highlights how commonly used antidepressants that modulate serotonin signaling might have previously unappreciated effects on immune function. This could potentially explain some of the variability in treatment response and side effect profiles of these medications, while also opening new avenues for therapeutic development targeting both psychological and inflammatory conditions 8 .
Despite these significant advances, numerous questions remain:
Ongoing research continues to explore these questions, potentially leading to novel treatments for autoimmune diseases, mood disorders, and cancer immunotherapy approaches 8 .
| Cell Type | SERT Expression | TPH-1 Expression | 5-HT Storage | Regulated Release |
|---|---|---|---|---|
| Immature DCs | Low | No | Minimal | No |
| Mature DCs | High | No | Significant (LAMP-1+ vesicles) | Yes (Ca2+-dependent) |
| Resting T-cells | Not detected | No | Not applicable | No |
| Activated T-cells | Not detected | Yes (inducible) | Not applicable | Not determined |
Data source: 8
The discovery of serotonin-mediated signaling between dendritic cells and T-cells represents a paradigm shift in our understanding of immune regulation. This research, conducted in 2005, revealed unexpected complexity in how our body's defense systems communicate, using the same chemical language as our brains 8 .
As research continues to unravel the implications of this finding, we move closer to a more integrated understanding of human health that bridges the artificial divisions between neurology, psychiatry, and immunology. The dialogue between our immune and nervous systems appears far more intimate and sophisticated than previously imagined, opening exciting possibilities for future therapeutic innovation 8 .