“Early to bed and early to rise makes one healthy, wealthy and wise.”
Day and night have existed for as long as the earth and sun- since before the beginning of life forms. So, it is not surprising that a large number of organisms, including all eukaryotes, have evolved considering day and night cycles. These changes that happen at physical, mental, behavioral, and molecular levels are referred to as circadian rhythms. Scientists have studied circadian rhythms for decades, and recently, Jeffrey C. Hall, Michael Rosbash, and Michael W. Young, who uncovered major genes responsible for circadian rhythms, were awarded the Nobel Prize. Common examples of the effects of circadian rhythm include body temperature, wakefulness, sleepiness, and hormonal activity.
The central circadian proteins include BMAL1 (Brain and Muscle ARNT-Like 1) and CLOCK (Circadian Locomotor Output Cycles Kaput), which are present in all mammalian cells and help in keeping track of the 24-hour cycle. They are ultimately controlled by sunlight since the presence of light triggers the day cycle that eventually wanes with darkness giving rise to the night cycle. Over the years, scientists discovered various levels of molecular regulation ranging from transcriptional and histone level regulation to chromosomal organizations, but the circadian proteins BMAL1 and CLOCK continue to remain centrally responsible for bodily effects.
In this article, we are more interested in seeing how immune cells, specifically T and B lymphocytes are affected by the circadian rhythms and what implications it has on the immune response.
Lymph nodes spread out all over the human body and act as local immune activation sites. For a long time, it was believed that just like blood flows through the blood vessels continuously, lymphocytes would also be constantly circulating through lymph vessels. But Druzd et al proved that that’s not the case. In fact, the number of lymphocytes one might find in the lymph nodes depends on the time of the day, and ultimately, is directly controlled by the circadian clock!
In the bloodstream, the number of lymphocytes found during the day is much higher than at night. In lymph nodes, the highest number of lymphocytes were found at the beginning of nighttime (an hour after an absence of light) while these numbers remained low during the daytime (daylight hours). As expected, when researchers deleted the BMAL1 gene, this rhythmic change of cell numbers in lymph nodes was lost, indicating that circadian rhythms directly influence lymphocyte numbers.
Now the question arises, how does the circadian clock regulate lymphocyte numbers? We know that lymphocytes smartly move around vasculature using chemokines (for sensing) and adhesion molecules (for latching on and rolling). It is these chemokines and adhesion molecules that are regulated by the circadian genes! Druzd et al showed that the expression of an important lymphocyte chemokine receptor, CCR7, also peaked at the onset of nighttime. Deleting the gene coding for CCR7 led to a loss of rhythmicity (i.e., change with the passage of day and night). This was not limited to just lymphocytes – the expression of CCL21 (ligand for CCR7) and ICAM-1 (adhesion molecule) in the microenvironment of lymph nodes also changed rhythmically on the deletion of that gene.
Aside from chemokine gradients, the S1P-S1PR axis also plays an important role in lymphocyte egress (exit from lymph nodes). Sphingosine-1-phosphate receptors (S1PR) are a class of receptors expressed on lymphocytes that sense sphingosine-1-phosphate gradients which help them to travel out of the lymph nodes and into the tissues through efferent lymph vessels. Hence, S1P-S1PR interplay is essential especially for homing and trafficking of lymphocytes. The researchers showed that expression of S1PR was highest during the day hours while it dipped into the night – just as one might expect from the previous observations. Again, deleting BMAL1 leads to loss of this rhythmic expression, hence confirming that S1PR is regulated by the circadian clock too.
The researchers also noticed that lymphocytes (T cells) in the lymph nodes fluctuated in phase with migratory dendritic cells, the major antigen-presenting cells. So, can the immune cell numbers at a particular time of day directly influence immune activation? The next set of experiments they performed showed that the immune response varied depending on the circadian clock, with nighttime immunization having a significantly more adverse effect than daytime. Another study found that sleep-deprived mice had lower expression of genes related to immune activation and antigen presentation but had no effect on T cell proliferation or antibody production.
Circadian rhythms have been and continue to be explored extensively in every domain of human physiology. Their control over lymphocyte trafficking through lymph nodes is a good example of their widespread influence on every aspect of our body. A better understanding of the relationship between circadian rhythms and immunology can drastically improve how we treat infections and conduct immunizations & immunotherapies.
- Druzd D, Matveeva O, Ince L, Harrison U, He W, Schmal C, Herzel H, Tsang AH, Kawakami N, Leliavski A, Uhl O, Yao L, Sander LE, Chen CS, Kraus K, de Juan A, Hergenhan SM, Ehlers M, Koletzko B, Haas R, Solbach W, Oster H, Scheiermann C. Lymphocyte Circadian Clocks Control Lymph Node Trafficking and Adaptive Immune Responses. Immunity. 2017 Jan 17;46(1):120-132. doi: 10.1016/j.immuni.2016.12.011.
- Cornelia Tune, Martin Meinhardt, Kathrin Kalies, Rene Pagel, Lisa-Kristin Schierloh, Julia Hahn, Stella E. Autenrieth, Christiane E. Koch, Henrik Oster, Andrea Schampel, Juergen Westermann, Effects of sleep on the splenic milieu in mice and the T cell receptor repertoire recruited into a T cell dependent B cell response, Brain, Behavior, & Immunity – Health, Volume 5, 2020, https://doi.org/10.1016/j.bbih.2020.100082.
- Rijo-Ferreira, F., Takahashi, J.S. Genomics of circadian rhythms in health and disease. Genome Med 11, 82 (2019). https://doi.org/10.1186/s13073-019-0704-0
P.S. Coincidentally, Schiermann group published a follow up study the day this blog was published in Nature Immunology in which they focused on exploring how migration of dendritic cells into lymph vessels is controlled by circadian rhythms.
Article author: Kevin Merchant. Kevin is a MS student at LMU Munich, Germany, who is passionate about Immunology and writing. He aims to simplify latest research so that it becomes accessible to all.
Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.
Check out Antibuddies’ blog post “Goodnight, Sleep tight, don’t take your immunity light”.Tweet