EDITOR'S CHOICE IN IMMUNOLOGY
People often feel tired when they get sick, and researchers think that the cytokines helping fight infection may induce sleepiness. If immune-system activation can affect sleep, might the converse be true—do sleep cycles affect the immune system? Erol Fikrig and colleagues at the Yale University School of Medicine isolated some of the molecular players in both the circadian and the innate immune systems. They showed that the strength of some immune responses was indeed affected by the time of day.
First, they looked at mice lacking a functional Per2 gene, which helps control the master circadian clock in the brain. Without a working copy, the mouse’s clock was altered, along with the expression of the Toll-like receptor 9 (TLR9), which is part of the innate immune response and detects the presence of bacterial or viral DNA in the cytoplasm of infected cells. Co-first authors Adam Silver and Alvaro Arjona tracked the expression of TLR9 and saw it change over the course of a 24-hour cycle in mice. Tissue samples from spleen, as well as antigen-presenting cells, such as macrophages and B cells, expressed the highest levels of TLR9 during the most active point of the day, which in the case of the mouse is at night. “At the tissue level there are a lot of particular TLR9 rhythms,” says Silver.
Then the investigators zoomed in on what was happening at the DNA level. They followed the activity of two circadian proteins, which bind together to form a transcription factor that turns on circadian-regulated genes. They found that this circadian transcription factor bound to the TLR9 gene’s promoter region and activated its expression, suggesting that TLR9 expression was regulated to a certain degree by circadian rhythms and offering a molecular explanation for TLR9’s cyclically fluctuating abundance in the cell.
To take their experiments even further, the team tested whether these fluctuating expression levels might actually have an impact on normal immune functions. They vaccinated mice at different times during their light-day cycles and tested how well the vaccine protected the mice. Although TLR9 is part of the innate immune system, which was thought less important in generating long-term immunity than the adaptive system, recent research suggests that activation of the innate system is essential for the full development of adaptive vaccine immunity. Indeed, Fikrig’s group showed that mice immunized during their time of greatest activity, when the amount of TLR9 peaked, had stronger immune reactions to the synthetic bacterial DNA-like fragments.
Many circadian researchers are trying to demonstrate the real-world applications of their work, says circadian biologist Bert Maier of the Charité University Hospital in Berlin. The work from Fikrig’s group, he says, “is very inspiring.”
A.C. Silver et al., “The circadian clock controls Toll-like receptor 9-mediated innate and adaptive immunity,” Immunity, 36:251-61, 2012.