Influence of circadian clocks on adaptive immunity and vaccination responses
Summary
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 modelling approaches, the authors of this article published in Nature Communications, led by GCIR member Professor Christoph Scheiermann, 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, the authors 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.
Full article: https://doi.org/10.1038/s41467-023-35979-2
Why is it important?
Circadian rhythms have emerged as a potent regulator of immune function. Diurnal rhythms have been characterized in multiple aspects of innate immunity, where they can alter the magnitude of immune responses. Here the authors investigated the mechanisms underlying diurnal rhythms in the generation of adaptive immunity. Using a combination of experimental and mathematical modelling approaches, they investigate how rhythms in cell migration, activation, and effector responses of different cell types interact to generate daily time periods of heightened immune reactivity.
The authors saw rhythmicity preserved in vaccination responses with a single dose, meaning that their findings are of direct public health relevance. Particularly in cases of limited vaccine availability or an urgent need for high levels of protective immunity, as currently observed in the SARS-CoV-2 pandemic, efficiently exploiting rhythmicity could optimize vaccination regimes. Additionally, given that human and mouse rhythms exhibit analogous peaks and troughs in their respective behavioural activity and rest phases, it would thus be important for clinical studies to include and report time-of-day as a critical variable for further investigations and potential improvement of treatment efficacy.