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Ince, Louise Madeleine; Barnoud, Coline; Lutes, Lydia Kay; Pick, Robert; Wang, Chen; Sinturel, Flore; Chen, Chien-Sin; de Juan, Alba; Weber, Jasmin; Holtkamp, Stephan J.; Hergenhan, Sophia Martina; Geddes-McAlister, Jennifer; Ebner, Stefan; Fontannaz, Paola; Meyer, Benjamin; Vono, Maria; Jemelin, Stéphane; Dibner, Charna; Siegrist, Claire-Anne; Meissner, Felix; Graw, Frederik; Scheiermann, Christoph (2023): Influence of circadian clocks on adaptive immunity and vaccination responses. Nature Communications, 14 (1). ISSN 2041-1723

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Abstract

The adaptive immune response is under circadian control, yet, why adaptive immune reactions continue to exhibit circadian changes over long periods of time is unknown. Using a combination of experimental and mathematical modeling approaches, we show here that dendritic cells migrate from the skin to the draining lymph node in a time-of-day-dependent manner, which provides an enhanced likelihood for functional interactions with T cells. Rhythmic expression of TNF in the draining lymph node enhances BMAL1-controlled ICAM-1 expression in high endothelial venules, resulting in lymphocyte infiltration and lymph node expansion. Lymph node cellularity continues to be different for weeks after the initial time-of-day-dependent challenge, which governs the immune response to vaccinations directed against Hepatitis A virus as well as SARS-CoV-2. In this work, we present a mechanistic understanding of the time-of-day dependent development and maintenance of an adaptive immune response, providing a strategy for using time-of-day to optimize vaccination regimes.

The adaptive immune response is under circadian control, yet, why adaptive immune reactions continue to exhibit circadian changes over long periods of time is unknown. Using a combination of experimental and mathematical modeling approaches, we show here that dendritic cells migrate from the skin to the draining lymph node in a time-of-day-dependent manner, which provides an enhanced likelihood for functional interactions with T cells. Rhythmic expression of TNF in the draining lymph node enhances BMAL1-controlled ICAM-1 expression in high endothelial venules, resulting in lymphocyte infiltration and lymph node expansion. Lymph node cellularity continues to be different for weeks after the initial time-of-day-dependent challenge, which governs the immune response to vaccinations directed against Hepatitis A virus as well as SARS-CoV-2. In this work, we present a mechanistic understanding of the time-of-day dependent development and maintenance of an adaptive immune response, providing a strategy for using time-of-day to optimize vaccination regimes.
01 30 2023 476 35979 1 10.1007/springer_crossmark_policy link.springer.com false 16 July 2021 11 January 2023 30 January 2023 The authors declare no competing interests. https://creativecommons.org/licenses/by/4.0 https://creativecommons.org/licenses/by/4.0 10.1038/s41467-023-35979-2 20230130060258119 https://www.nature.com/articles/s41467-023-35979-2 https://www.nature.com/articles/s41467-023-35979-2.pdf https://www.nature.com/articles/s41467-023-35979-2.pdf https://www.nature.com/articles/s41467-023-35979-2 Science K Man 354 999 2016 10.1126/science.aah4966 Man, K., Loudon, A. & Chawla, A. Immunity around the clock. Science 354, 999–1003 (2016). Immunology M Baxter 161 261 2020 10.1111/imm.13166 Baxter, M. & Ray, D. W. Circadian rhythms in innate immunity and stress responses. Immunology 161, 261–267 (2020). J. Exp. Med. M Palomino-Segura 218 e20200798 2021 10.1084/jem.20200798 Palomino-Segura, M. & Hidalgo, A. Circadian immune circuits. J. Exp. Med. 218, e20200798 (2021). Nat. Rev. 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