Circadian rhythms in adaptive immunity and vaccination

Abstract

Adaptive immunity allows an organism to respond in a specific manner to pathogens and other non-self agents. Also, cells of the adaptive immune system, such as T and B lymphocytes, can mediate a memory of an encounter with a pathogen, allowing a more efficient response to a future infection. As for other aspects of physiology and of the immune system, the adaptive immune system is regulated by circadian clocks. Consequently, the development, differentiation and trafficking between tissues of adaptive immune cells have been shown to display daily rhythms. Also, the response of T cells to stimuli (e.g. antigen presentation to T cells by dendritic cells) varies according to a circadian rhythm, due to T cell-intrinsic mechanisms as well as cues from other tissues. The circadian control of adaptive immune response has implications for our understanding of the fight against pathogens as well as auto-immune diseases, but also for vaccination, a preventive measure based on the development of immune memory.

The Influence of Time of Day of Vaccination with BNT162b2 on the Adverse Drug Reactions and Efficacy of Humoral Response against SARS-CoV-2 in an Observational Study of Young Adults

“…An increasing body of evidence from both academic and clinical studies shows that time-of-day exposure to antigen might significantly alter and modulate the development of adaptive immune responses [ 20 ]. Indeed, circadian rhythmicity of dendritic-, T- and B-cells was reported on every level of their function, starting from development [ 20 , 39 ] through trafficking [ 22 , 40 , 41 ], ending on activation [ 21 , 42 , 43 ] and exhaustion [ 44 ]. Recently, Holtkamp et al [ 41 ] indicated that migration of DCs into skin lymphatics is rhythmic and under the direct control of the circadian clock gene BMAL1 .…”

“…Another promising path towards the improvement of vaccine efficacy is related to findings in the field of circadian rhythms of the immune system. Although, for many years, it has been widely recognized that significant fluctuations in the function of the innate immune system exists [ 16 ], such as time-of-day dependent amount of cytokine release by tissue macrophages upon LPS stimulation [ 17 , 18 ] or neutrophil recruitment [ 19 ], recent experiments shed new light on the potential impact of circadian rhythms on adaptive immune responses [ 20 ]. Notably, as many as 6% of all protein-coding transcripts in murine CD8 + T cells are in sync with the magnitude of their response to vaccination under modulation of the molecular clock [ 21 ].…”

“…Data on whether the time-of-day difference in the exposure to antigens during vaccination results in a varying efficacy of mounting of the adaptive immune responses are very scarce and in humans consists of as little as ~10 trials [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. The limited number of existing trials, along with their heterogeneity in terms of both age, overall health status of participants and studied vaccines (against influenza, hepatitis A and B, tuberculosis [ 20 ]), lead to the mixed results in regard to effectiveness of mounting humoral responses and characteristics of adverse drug reactions (ADR) between morning versus afternoon vaccinations. So far, two studies have assessed immunological response against SARS-CoV-2 in the context of circadian rhythms.…”

Macrophage Meets the Circadian Clock: Implication of the Circadian Clock in the Role of Macrophages in Acute Lower Respiratory Tract Infection

“…Diet (i.e., nutrition), physical exercise, and aging progression has been revealed to modulate the phenotype of macrophages, defining systemic inflammatory status (Olefsky and Glass, 2010;Dall'Asta et al, 2012;Kizaki et al, 2012;Linehan and Fitzgerald, 2015;Davanso et al, 2020;Sitlinger et al, 2020;De Maeyer and Chambers, 2021;Duong et al, 2021). It has begun to be accepted that both the quantity and quality of immune cells including monocytes/macrophages exhibit a robust daily oscillation (Curtis et al, 2014;Leach and Suzuki, 2020;Shimba and Ikuta, 2020;Waggoner, 2020;Cermakian et al, 2021). The accumulating evidence illustrates the molecular mechanisms underlying the biological clock oscillators regulate temporal diversity of immune activities in accordance with cyclic environmental cues (e.g., light-dark cycles and temperature fluctuation) and behavioral rhythms (e.g., sleep-wake cycles, feeding-fasting cycles), which orchestrates the temporal regulation of immune homeostasis.…”

Chronoimmunology: from preclinical assessments to clinical applications

“…Cermakian et al [9] focus on the circadian regulation of the adaptive immune system and the responses of T cells to antigen presentation by dendritic cells, due to T cell-intrinsic mechanisms as well as cues from other tissues. In a complementary paper, Gray and Gibbs [10] describe how circadian clocks affect homeostatic aspects of adaptive immunity (such as lymphocyte trafficking and development of T lymphocyte subsets) as well as adaptive responses to acute challenges, again considering the interaction of the cellular clockwork machinery and extrinsic rhythmic signals.…”