In this proposal we present ambitious and innovative concepts and technologies that will have significant scientific impact for the understanding into the modulation of the immune system in health and disease. Circadian timing in the adaptive immune system has recently gained attention as an important gating mechanism for immune responses. Leukocyte trafficking to and from the lymph node is highly time-of-day dependent, and this rhythm can greatly influence the strength of the adaptive immune response. Lymph nodes serve as draining sites for peripheral tissues but whether rhythms in these upstream sites govern downstream lymph node responses are completely unknown. Our hypothesis is that in the skin, which provides an epithelial cell barrier to the environment, circadian dynamics in leukocyte immigration, egress, proliferation and/or cell death contribute to a functional epithelial barrier. The mechanisms of this phenomenon are completely unexplored. Furthermore, the relevance of this rhythmicity for the body is unclear. The impact of this proposal lies in the meticulous analysis of circadian immune cell dynamics of the biggest organ of the body, the skin. We propose to unravel the mechanism and interactions of circadian leukocyte dynamics in this tissue using a strong and inter-disciplinary team of researchers (in proteomics, circadian biology, the microbiome and mathematical modeling), rigorous genetic models (lineage-specific and inducible knock-outs and knock-ins) and technically innovative experimental approaches (lineage-specific circadian phosphoproteomics and circadian, single-cell sequencing of skin leukocytes, combined approaches of genetic, pharmacological and local surgical ablation of sympathetic tone as well as site-specific analyses of the microbiome on skin leukocyte oscillations). The quantification and mathematical modeling of leukocyte dynamics in the skin will provide us with the relevant information on the best time and target of adjuvant delivery and allow for better vaccination design. Thus, our research – intersected between the domains of immunology and chronobiology – will go beyond the current state of the art and will provide an in-depth understanding of circadian rhythmicity in immune cell function in the skin, which we aim to harness for the future development of time-tailored therapies targeting adaptive immune responses.
In clinical practice, circadian oscillations are generally not considered. Our data published in Nature 2023 goes beyond the current state of the art, indicating that time of day should matter in clinical practice, such as when treating tumor patients. We are expecting to provide further molecular insights into the steady-state immune oscillations in the skin until the end of the project and aim to leverage this in better vaccine design. We have now provided further evidence for time-of-day changes in skin anti-tutor immunity by showing that antibodies directed against immune-checkpoint inhibitors provide time-of-day benefits, based on their time of infusion (Cell 2024). This is unexpected, given that these drugs exhibit long half-lives. We are now investigating the underlying mechanisms.
