Circadian rhythms in leukocyte recruitment to tissues

Leukocyte recruitment from blood to tissues is a critical step of the immune system to protect against pathogens and provide tissue repair. While myeloid cell recruitment is a hallmark in inflammatory conditions, lymphocyte recirculation through tissues is an important feature of immune surveillance of an organism at steady‐state. Thus far, various molecules have been implicated in these migratory processes including chemokines and adhesion molecules. However, how this fundamental process of immunity is being regulated at the organismal level at different times is unknown. Here, we describe mechanisms that govern a non‐continuous but oscillatory behavior in the infiltration of myeloid and lymphoid cells to different tissues in the mouse. We screened multiple adhesion molecules and chemokine receptors on various leukocyte subpopulations in addition to molecules expressed by endothelial cells in vascular beds of multiple organs. Our data indicate the existence of a leukocyte‐ and tissue‐specific oscillatory molecular signature in the expression of pro‐migratory factors. Specifically, we present data demonstrating that robust circadian oscillations, exhibiting a period length of ~24h, occur in cellular numbers in murine lymph nodes, showing a ~2‐fold difference with a trough at the onset of the behavioral rest phase (light) and a peak at the onset of the active phase (dark). Oscillations were observed in the capacity of lymphocytes to home to lymph nodes, peaking at the onset of the activity phase. Using lineage‐specific genetic ablation of circadian rhythmicity in T and B cells we demonstrate this to be dependent on both lymphocyte and endothelial oscillations in cell surface receptors. We detected similar oscillations in the capacity of lymphocytes to exit lymph nodes, exhibiting a ~3‐fold difference in the amount of cells in efferent lymphatic vessels. Egress could be modulated in a rhythmic manner acutely by pharmacological interventions as well as chronically with the help of lymphocyte‐specific genetic approaches. Taken together, our data show discrete tissue and leukocyte mechanisms that control rhythmic leukocyte recruitment to organs and provide new insights into the temporal control of innate and adaptive immunity. Support or Funding Information Funded by the European Research Council (CIRCODE) and the German Research Foundation (Emmy Noether SCHE 1645/2‐1 and SFB914 projects B09 and Z03).