The effectiveness of vaccinations and immunotherapies depends on the periodic migration of immune cells from organs to lymph nodes, where these cells process and present foreign proteins to trigger immune responses against specific targets.

Immune function is at its peak just before the activity of the day starts—early morning in humans and mid-afternoon for nocturnal creatures like mice—as demonstrated in a study performed by scientists at the University of Geneva (UNIGE) in Switzerland and the Ludwigs-Maximilians University (LMU) in Germany.

The study focused on the migration of immune cells called dendritic cells from the skin to the lymph nodes that oscillates over a 24-hours period, providing evidence that the activation of the immune system is modulated according to the time of day.

The findings are reported in an article titled, “Circadian clocks guide dendritic cells into skin lymphatics,” published in Nature Immunology. These results suggest the time of day should be considered when administering vaccines or immunotherapies to increase their effectiveness.

Immune dendritic cells (green) migrate from the skin into lymphatic vessels (red) to trigger an adaptive immune response. This process depends on the time of day. Blood vessels are in blue. [Source: UNIGE/Christoph Scheiermann]
The innate immune system responds immediately but its actions are neither targeted nor stored in the system’s memory whereas the adaptive or acquired immune system takes time to develop and caters its response to a specific target, say an infectious agent, and stores the details of the response in long-term memory so that it can be called upon if a similar situation arises again.

“The adaptive immune system takes weeks to form a response specific to a given pathogen. This response then lasts for a long time thanks to a cellular memory mechanism,” said Christoph Scheiermann, PhD, a professor in the department of pathology and immunology in the Geneva Centre for Inflammation Research (GCIR) at UNIGE Faculty of Medicine, and a corresponding author of the new study. “This is typically the mechanism at work during vaccination against a virus, for example.”

The researchers focused on the migration of dendritic cells from the skin into lymphatic vessels to understand how the time of day influences immunity since it is a central mechanism of the adaptive immune response. Dendritic cells migrate from the skin and other organs through the lymphatic vessels to the lymph nodes, where they present antigens—fragments of foreign material. This is the first step in mounting a targeted immune response.

The team analyzed the migratory capacity of dendritic cells in normal mice four times a day and compared the process to that in mice without functional circadian clocks.

“For cell migration to take place correctly, not only the dendritic cells but also the lymphatic vessel cells must respond to a circadian rhythm,” said Stephan Holtkamp, PhD, a researcher at the Biomedical Center of the Ludwig-Maximilian University and first author of this study.

For the rhythmic diurnal migration of the dendritic cells that peaks at the start of the day, the researchers showed, the circadian clock mechanism must function both within the migrating dendritic cells and in the cells that line the skin’s lymphatic vessels (skin lymphatic endothelial cells, LECs) in mice, or else migration trudges along in continuous slow motion.

To identify molecules regulating this rhythmic trafficking, the researchers conducted experiments on human skin cells taken from patients at different times of the day. They showed that the chemokine CCL21, and cell adhesion molecules regulate the rhythm in both mice and humans.

“We identified numerous molecules, in particular chemokines, which are involved in the migratory process and whose expression is regulated by circadian clocks,” said Scheiermann. “The same molecules were found in human and mouse cells with an inverted rhythm corresponding to the life habits of the two species, nocturnal for rodents, diurnal for humans. This confirms that this rhythm is governed by natural activity according to the alternation of day and night.”

The authors also showed that if the immune system is stimulated at different times of the day the dendritic cells continue to migrate rhythmically with a peak in the morning.

This could indicate that such migratory rhythms make the best use of the available bioenergy, maximizing protection through an immune system that is on high alert when the risk of exposure to infectious agents is greater and dampening down costly defenses when the organism is at rest and less likely to be exposed to pathogens. However, such conclusions will need more experiments.

The importance of circadian clocks in regulating the immune system is only just beginning to be revealed. The authors concluded, “As this process is fundamental for the generation of adaptive immunity, it should prove useful to exploit in vaccination and immunotherapeutic regimens, considering that rhythmicity in innate and adaptive immune responses is maintained in inflammatory reactions.”