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Voluntary action is a fundamental element of self-consciousness. The readiness potential (RP), a slow drift of neural activity preceding self-initiated movement, has been suggested to reflect neural processes underlying the preparation of voluntary action; yet more than fifty years after its introduction, interpretation of the RP remains controversial. Based on previous research showing that internal bodily signals affect sensory processing and ongoing neural activity, we here investigated the potential role of interoceptive signals in voluntary action and the RP. We report that (1) participants initiate voluntary actions more frequently during expiration, (2) this respiration-action coupling is absent during externally triggered actions, and (3) the RP amplitude is modulated depending on the respiratory phase. Our findings demonstrate that voluntary action is coupled with the respiratory system and further suggest that the RP is associated with fluctuations of ongoing neural activity that are driven by the involuntary and cyclic motor act of breathing. Voluntary action and free will have been associated with cortical activity, referred to as “the readiness potential” that precedes self-initiated actions by about 1 s. Here, the authors show that the involuntary and cyclic motor act of breathing is coupled with voluntary action and the readiness potential.

Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses 1 , 2 . Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood 3 , 4 . Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans. Chronopharmacological targeting of the involved factors abrogates circadian migration of DCs. We identify cell-intrinsic circadian oscillations in skin lymphatic endothelial cells (LECs) and DCs that cogovern these rhythms, as their genetic disruption in either cell type ablates circadian trafficking. These observations indicate that circadian clocks control the infiltration of DCs into skin lymphatics, a process that is essential for many adaptive immune responses and relevant for vaccination and immunotherapies. Scheiermann and colleagues show that circadian clocks control the infiltration of dendritic cells into skin lymphatics in mice and humans, with a peak migration to the lymph nodes during the rest phase.

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. Circadian rhythms have been shown to influence immune responses, but it is unclear whether this influences responses to vaccines. Here the authors show that dendritic cells migrate in a circadian rhythm meaning that interactions with T cells are altered leading to differential vaccine responses.

Rare genetic disorders, often characterized by their low prevalence and complexity, present significant challenges to both patients and healthcare providers. These conditions can manifest in various ways, affecting multiple organ systems and often resulting in severe disabilities or life-threatening complications. While the genetic basis of these disorders is well-established, recent research has shed light on the role of immunome dysregulation in their pathogenesis. Components of the immunome: The immunome encompasses the complex network of genes, proteins, and cells involved in immune system function. This includes immune cells (e.g., T cells, B cells), cytokines, antibodies, and Major Histocompatibility Complex (MHC) molecules. Immune responses: The immunome orchestrates immune responses against pathogens, foreign invaders, and aberrant cells, while also maintaining immune tolerance to self-antigens. Immunosuppressive therapies: Patients with rare genetic disorders and immunome dysregulation may benefit from immunosuppressive treatments to modulate excessive immune responses.

The immune system plays a critical role in protecting the body against pathogens and maintaining overall health. However, in certain conditions, the immune system can become dysregulated, leading to various disorders and diseases. Identifying the signatures or biomarkers associated with immune system dysregulation is crucial for understanding the underlying mechanisms, developing diagnostic tools, and designing targeted therapies. The immune system comprises a complex network of cells, tissues, and molecules that work together to defend the body. Immune system dysregulation refers to a disruption in the balance or coordination of immune responses, leading to an overactive or underactive immune system. Dysregulation can result from genetic factors, environmental triggers, infections, autoimmune disorders, or immunodeficiencies. Here, approaches for identifying signatures are highlighted.

The process of cancer immunosurveillance is a mechanism of tumour suppression that can protect the host from cancer development throughout its lifetime 1 , 2 . However, it is unknown whether the effectiveness of cancer immunosurveillance fluctuates over a single day. Here we demonstrate that the initial time of day of tumour engraftment dictates the ensuing tumour size across mouse cancer models. Using immunodeficient mice as well as mice lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8 + T cells exert circadian anti-tumour functions that control melanoma volume. Specifically, we find that rhythmic trafficking of DCs to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8 + T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80. As a consequence, cancer immunotherapy is more effective when synchronized with DC functions, shows circadian outcomes in mice and suggests similar effects in humans. These data demonstrate that the circadian rhythms of anti-tumour immune components are not only critical for controlling tumour size but can also be of therapeutic relevance. Rhythmic trafficking of dendritic cells to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8 + T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80.